U.S. patent application number 15/467713 was filed with the patent office on 2017-07-06 for abuse deterrent immediate release biphasic matrix solid dosage form.
This patent application is currently assigned to SUN PHARMA ADVANCED RESEARCH COMPANY LTD.. The applicant listed for this patent is SUN PHARMA ADVANCED RESEARCH COMPANY LTD.. Invention is credited to Nitin Bhalachandra DHARMADHIKARI, Dilip SHANGHVI, Yashoraj Rupsinh ZALA.
Application Number | 20170189339 15/467713 |
Document ID | / |
Family ID | 54188809 |
Filed Date | 2017-07-06 |
United States Patent
Application |
20170189339 |
Kind Code |
A1 |
DHARMADHIKARI; Nitin Bhalachandra ;
et al. |
July 6, 2017 |
ABUSE DETERRENT IMMEDIATE RELEASE BIPHASIC MATRIX SOLID DOSAGE
FORM
Abstract
An abuse deterrent immediate release biphasic matrix solid
dosage form that releases the drug at a desired rate for quick
onset of action when a single unit or prescribed units of the
dosage form are orally administered but exhibits a reduced rate of
release when more than the prescribed number of units, are
administered.
Inventors: |
DHARMADHIKARI; Nitin
Bhalachandra; (Mumbai, IN) ; ZALA; Yashoraj
Rupsinh; (Mumbai, IN) ; SHANGHVI; Dilip;
(Mumbai, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SUN PHARMA ADVANCED RESEARCH COMPANY LTD. |
Mumbai |
|
IN |
|
|
Assignee: |
SUN PHARMA ADVANCED RESEARCH
COMPANY LTD.
Mumbai
IN
|
Family ID: |
54188809 |
Appl. No.: |
15/467713 |
Filed: |
March 23, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14667826 |
Mar 25, 2015 |
9642811 |
|
|
15467713 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2059 20130101;
A61K 9/2009 20130101; A61K 31/135 20130101; A61K 9/2031 20130101;
A61P 25/04 20180101; A61K 9/2013 20130101; A61K 9/2077 20130101;
A61K 9/2054 20130101; A61K 9/5026 20130101; A61K 9/4858 20130101;
A61K 9/485 20130101; A61K 9/2846 20130101; A61K 31/433 20130101;
A61K 31/137 20130101; A61K 9/4808 20130101; A61K 9/2081 20130101;
A61K 31/5517 20130101; A61K 31/167 20130101; A61P 25/24 20180101;
A61K 9/2027 20130101; A61K 9/4866 20130101; A61K 31/137 20130101;
A61K 2300/00 20130101 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 31/167 20060101 A61K031/167; A61K 31/433 20060101
A61K031/433; A61K 31/137 20060101 A61K031/137 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 26, 2014 |
IN |
1041/MUM/2014 |
Jul 23, 2014 |
IN |
2378/MUM/2014 |
Sep 13, 2014 |
IN |
2917/MUM/2014 |
Jan 8, 2015 |
IN |
74/MUM/2015 |
Claims
1. An abuse deterrent immediate release biphasic matrix solid
dosage form comprising: an intragranular phase comprising a mixture
of a drug susceptible to abuse and a reverse enteric polymer; an
extragranular phase; and an alkalizer, wherein the intragranular
phase further comprises a first part of the alkalizer and the
extragranular phase comprises a second part of the alkalizer.
2. The abuse deterrent immediate release biphasic matrix solid
dosage form according to claim 1 wherein the drug susceptible to
abuse and the reverse enteric polymer are melt extruded to form a
solid dispersion characterized by the absence of X-ray diffraction
peaks characteristic of the crystalline drug.
3. The abuse deterrent immediate release biphasic matrix solid
dosage form according to claim 1, further comprising an alcohol
dose dumping resistance polymer located only in the intragranular
phase.
4. The abuse deterrent immediate release biphasic matrix solid
dosage form according to claim 1, further comprising an alcohol
dose dumping resistance polymer located in both the intragranular
phase and extragranular phase.
5. The abuse deterrent immediate release biphasic matrix solid
dosage form according to claim 1, further comprising an alcohol
dose dumping resistance polymer that covers the intragranular
phase.
6. The abuse deterrent immediate release biphasic matrix solid
dosage form according to claim 5, wherein the alcohol dose dumping
resistance polymer is also present in the intragranular phase.
7. The abuse deterrent immediate release biphasic matrix solid
dosage form according to claim 6, wherein the alcohol dose dumping
resistance polymer is also present in the extragranular phase.
Description
[0001] This application is a Continuation application of U.S.
application Ser. No. 14/667,826, filed Mar. 25, 2015 and claims
benefit to Indian Application Nos. 74/MUM/2015, filed Jan. 8, 2015;
2917/MUM/2014, filed Sep. 13, 2014; 2378/MUM/2014, filed Jul. 23,
2014; and 1041/MUM/2014, filed Mar. 26, 2014.
BACKGROUND OF THE INVENTION
1. Field
[0002] The present invention relates to abuse deterrent immediate
release biphasic matrix solid dosage that releases the drug at a
desired rate for quick onset of action when a single unit or
prescribed units of the dosage form are orally administered but
exhibits a reduced rate of release when more than the prescribed
number of units, are administered. When an abuser, with the
objective of achieving a high blood concentration of the drug uses
multiple units of the dosage forms through multiple modes of abuse
such as extraction or ingestion, he encounters resistance of the
dosage form to release high amounts of the drug and provide high
blood concentration.
[0003] Abuse of prescription drugs is considered an epidemic. Abuse
of the prescription behavior may be for satisfying the craving for
an addictive drug. It may be for improvement of performance such as
use of steroids and stimulants. Prescription drugs may also be
abused for abetting suicides by taking multiple pills.
[0004] An abuser of prescription drugs seeking to satisfy the
craving for an addictive drug such as opioids, seeks a potent and
rapid "high" i.e. euphoria and this is obtained by achieving a high
blood concentration (high "C.sub.max") in a short time (T.sub.max)
(Katz et al (The American Journal of Drug and Alcohol Abuse,
37:205-257, 2011, Abreu, M. E., G. E. Bigelow, L. Fleisher, S. L.
Walsh, 2001, Effect of Intravenous Injection Speed on Responses to
Cocaine and Hydromorphone in Humans, Psychopharmacology, 154:76-84;
de Wit, H., B. Bodker, J. Ambre, 1992, Rate of Increase of Plasma
Drug Level Influences Subjective Responses in Humans,
Psychopharmacology, 107:352-358; and de Wit, H., S. Didish, J.
Ambre, 1993, Subjective and Behavioral Effects of Diazepam Depend
on Its Rate of Onset, Psychopharmacology, 112: 324-330). Extended
release dosage forms provide peak plasma concentration at a longer
time (T.sub.max) but because they are given at a lower frequency
for example once-a-day they contain a higher amount of drug than
immediate release or rapid release dosage forms. Therefore, they
are attractive to the abuser when the abuser can tamper with them
to destroy the controlled release properties. Thus, one-way to
deter misuse is to provide the medication in an extended release
form together with design features such as tamper resistance that
prevent the abuser from defeating the controlled release properties
or extracting the opioid from the dosage form in aqueous or organic
liquids. In April 2013, USFDA refused to approve generic versions
of Oxycontin extended release formulations that were not
tamper-resistant and thus susceptible to abuse. Therefore it is
essential to have design features that prevent the abuser from
taking a prescription dosage form and tampering it to produce a
form suitable for achieving a high C.sub.max in a short time
(T.sub.max) through oral administration or administration via fast
onset routes such as parenteral or nasal. Commonly the extended
release dosage form is indicated for chronic therapy, for example,
opioid extended release formulations are indicated for pain severe
enough to require daily around-the-clock treatment. Technology for
such tamper resistant dosage forms has been available for more than
a decade and has been used in recently commercialized opioid
products such as Oxcontin.RTM. ER Tablets (containing oxycodone
hydrochloride as the active ingredient). Examples of such abuse
deterrent dosage forms are described in U.S. Pat. Nos. 6,488,963,
7,776,314, 8,114,383, 8,309,060, 8,337,888, 8,075,872, 8,114,384,
8,192,722, 8,420,056, 8,507,001 and 8,298,581.
[0005] However, rapid release opioids are also required and are
prescribed by physicians when a quick onset of action is needed.
For example, Oxcontin.RTM. ER Tablets are available in strengths of
10, 15, 20, 30, 40, 60 and 80 mg of oxycodone base, whereas
immediate or rapid release Oxycodone Tablets are available in
strengths of 5, 7.5, 10, 15, 20 and 30 mg of oxycodone. In view of
the liking for a high C.sub.max and in view of development of
tolerance, chronic abusers graduate to higher and higher dosages of
the opioid. Therefore chronic abuser generally requires multiple
doses of an immediate or rapid release dosage form. Therefore,
dosage forms that release a drug susceptible to abuse rapidly may
be subject to abuse by administration of multiple pills.
[0006] In addition to opioids, multiple dosage forms of
antidepressants, antipsychotic and other CNS drugs are also widely
abused in suicidal attempts. Overdose refers to ingestion of a dose
greater than a usual dose. "Usual dose" as used herein means a dose
approved by a drug regulatory authority such as Food & Drug
Administration or prescribed by a physician for treatment or
prevention of a diseases condition or relief of symptoms thereof.
The high plasma levels of a drug candidate resulting from the
overdose, causes adverse effects often leading to medical emergency
and inconvenience to his or her family and the medical profession
involved. Death is often a consequence of serious overdosing. A
person's tolerance to overdose varies with age, state of health,
how the substance was consumed and other factors. Death may follow
immediately or more slowly if organs are permanently damaged.
[0007] A patient may ingest an overdose accidentally or through
intentional misuse. In case of accidental overdose, a person takes
a wrong drug or combination of drugs, in the wrong amount or at the
wrong time inadvertently. On the other hand, in case of intentional
misuse, a person takes an overdose to get `high` or to inflict
self-harm. The latter may be a cry for help or a suicide
attempt.
[0008] Use of medication is increasing world-wide. The United
States Food and Drug Administration (USFDA) has approved more than
10000. The reasons may be the introduction of vast number of agents
by the advanced pharmaceutical industry in addition to the wide
spectrum of diseases that increased demands for intensifying
therapeutic challenges. Most commonly, the patient benefits from
pharmaco-therapeutic interventions; however, adverse events,
ranging from minor side effects to death, may occur. Any deviation
from the intended beneficial effect of a medication results in a
drug related problem (DRP). (Al-Arifi et al., Saudi Pharmaceutical
Journal, January 2014, 22(1), 17-25).
[0009] It has been estimated that DRPs account for 17 million
emergency department (ED) visits and 8.7 million hospital
admissions annually in the United States. (Johnson et al., Archives
of Internal Medicine, October 1995, 155(18), 1949-56) Between 1995
and 2000, a probability model estimated that costs associated with
morbidity and mortality secondary to DRPs have more than doubled
from US$76.6 billion to more than US$177.4 billion. (Ernst et al.,
Journal of American Pharmacists Association, 2001 March-April,
41(2), 192-9). In United States of America, estimates on
drug-related visits to hospital emergency departments (ED) are
obtained from the Drug Abuse Warning Network (DAWN), which is a
public health surveillance system managed by the Substance Abuse
and Mental Health Services Administration (SAMHSA), U.S. Department
of Health and Human Services (HHS). The DAWN database as updated
till 2011 and it reports more than 500 different medications being
reported to be consumed accidentally leading the user to make
emergency visits. Out of these different medications, the majority
of the drugs being overdosed causing emergency situations are
mainly, antidepressants, analgesics, hypnotics and sedatives
(http://www.samhsa.gov/data/).
[0010] One or more DRPs may develop in a given patient after the
initial drug therapy. Although many DRPs can be resolved without a
major impact on patient's health, some of them can be associated
with significant morbidity and mortality. (Classen et al., Journal
of American Medical Aassociation, January 1997, 277 (4), 301-6).
Hepler et al defined DRP as an event or circumstance involving drug
treatment that actually or potentially interferes with the patients
experiencing an optimum outcome of medical care. They also
classified DRPs into eight general categories, which include
untreated indication, treatment without indication, improper drug
selection, too little drug, too much drug, noncompliance, adverse
drug reaction (ADR), and drug interaction (Hepler et al., American
Journal of Hospital Pharmacy, 1990 March, 47(3), 533-43).
[0011] The most common class of drugs reported in literature that
cause drug related problems due to intention or unintentional
overdose are tricyclic antidepressants (TCS), benzodiazepines,
analgesics like paracetamol, aspirin and opioids.
[0012] Kerr et al. reviewed the overdose because of tricyclic
antidepressants. Overdoses of tricyclic antidepressant are among
the commonest causes of drug poisoning seen in accident and
emergency department. Complications of tricyclic antidepressant
overdose reported were sinus tachycardia, ECG changes, Heart block,
Vasodilatation, Hypotension, Cardiogenic shock and Ventricular
fibrillation. CNS related complications include Drowsiness, Coma,
Convulsions, Pyramidal signs, Rigidity, Delirium, Respiratory
depression, Ophthalmoplegia. Different anticholinergic effects
observed were Dry mouth Blurred vision, dilated pupils, Urinary
retention, absent bowel sounds, Pyrexia, Myoclonic twitching. (Kerr
et al., Emergency Medicine Journal, 2001, 18, 236-241).
[0013] As reported, 20% of deaths were associated with accidental
deaths due to overdose whereas 80% were associated with intentional
deaths, suggesting that most deaths from antidepressant drugs are
due to suicide. Tricyclic antidepressants are associated with a
higher number of accidental and intentional deaths, and
significantly more accidental (P50.0001) and intentional (P50.001)
deaths were observed with the tricyclics than would be expected
when standardized for the number of prescriptions. The SSRIs were
associated with significantly fewer accidental (P50.0001) and
intentional (P50.0001) deaths than would be expected when
standardized for the number of prescriptions. For the other
antidepressant drugs there was no significant difference (Survjit
cheeta et al., British journal of Psychiatry, 2004, 184:41-47).
Therefore SSRI (selective serotonin reuptake inhibitors) are
considered to be less toxic than in overdose than TCA (tricyclic
antidepressants). Venlafaxine a SSRI was studied. (Whyte et al.,
Quarterly journal of medicine, 2003, 96, 369-374)
[0014] Benzodiazepines are among the most frequently prescribed
drugs worldwide. This popularity is based not only on their
efficacy but also on their remarkable safety. Pure benzodiazepine
overdoses usually induce a mild to moderate central nervous system
depression; deep coma requiring assisted ventilation is rare, and
should prompt a search for other toxic substances. The severity of
the CNS depression is influenced by the dose, the age of the
patient and his or her clinical status prior to the ingestion, and
the congestion of other CNS depressants. In severe overdoses,
benzodiazepines can occasionally induce cardiovascular and
pulmonary toxicity, but deaths resulting from pure benzodiazepine
overdoses are rare. (Gaudreault P. et al., Drug Safety, 1991
July-August, 6(4), 247-65).
[0015] It has been reported that between 1993 and 2004, 2,196
poisoning deaths occurred involving paracetamol. Overdose is one of
the most frequent indications for patients to be admitted to the
medical wards. In the recent past, three changes have occurred
which might influence self-poisoning. First, a change in available
paracetamol packs size. Secondly, the introduction of new
antidepressant drugs some of which, in particular the SSRI group,
are perceived as being less toxic in overdose, has resulted in a
more than two-fold increase in prescriptions. Thirdly an in
increasing use of drugs of abuse, specifically opiates, which is
itself associated with an increase in self-harm and suicide.
(Bateman et al., Quarterly Journal of Medicine, 2003, 96,
125-132).
[0016] According to Bohmert et. al, there was increase in rate of
unintentional overdose in USA by 124% largely because of the
prescription opioids. Higher prescribed doses increase the risk of
drug overdose among individuals treated with opioids for chronic
non-cancer pain (Bohmert et al., The journal of the American
medical association, 6 Apr. 2011, vol 305, No. 13).
[0017] It is estimated that 52% deaths were caused due overdoses of
anticoagulants, insulin and oral hypoglycemic, cardiac glycosides
or thyroxine out of which 50% were accidental (D Gunnell et al.,
Emergency Medicine Journal, 2004, 21, 35-38).
[0018] Brune et all report that aspirin and paracetamol are lethal
when taken at overdose. They are best-selling OTC drugs and can
pose a significant risk to the consumer who is unaware of the
toxicity of these drugs (Brune et al., Current Rheumatology Reports
February, 2009, Volume 11, Issue 1, 36-40).
[0019] For reasons discussed hereinabove, particularly preventing
intentional abuse for addiction or suicidal attempt or
unintentional/accidental overdosing. there is a need for an abuse
deterrent solid dosage form that allows the release of the drug at
a desirable rate when a single or prescribed number of units of the
dosage form are orally administered but exhibits a reduced rate of
release when more than single unit or prescribed number of units,
are simultaneously orally administered. The present inventors have
discovered biphasic matrix solid dosage forms that can resolve
atleast one of the modes of abuse of immediate release solid dosage
form such as
[0020] a. intentional abuse of overdosing or multiple unit
administration by an addict or by a subject having suicidal
intention,
[0021] b. intentional abuse of extraction from multiple unit
administration by an addict or by a subject having suicidal
intention
[0022] c. unintentional or accidental overdosing,
[0023] d. concomitant alcohol consumption and resultant
drug-alcohol interaction
[0024] e. intentional abuse by nasal, parenteral, rectal or oral
route
[0025] f. separating two phases by physical means with an intention
to abuse
[0026] Particular embodiments have been discovered that
simultaneously resolve two or three or more of the above modes of
abuse. Further embodiments of biphasic matrix solid dosage forms
have been discovered that are resistant to physical means for
separating the two phases with an intention to abuse. The physical
means may be crushing the dosage form followed by size
separation.
SUMMARY OF THE INVENTION
[0027] The abuse deterrent immediate release solid biphasic matrix
dosage form of the present invention comprises a drug susceptible
to abuse and a release inhibiting agent such that when more than
the prescribed number of units of the dosage form are orally
administered, the release is inhibited as compared to the release
when a single unit of the dosage form is orally administered. The
term `release inhibiting agent` as used herein refers to a
substance or a combination thereof, that functions to inhibit the
release of the drug susceptible to abuse in gastric fluids only
when more than the prescribed number of units of the dosage form
are orally administered. In preferred embodiment, the release
inhibiting agent is a combination of one or more reverse enteric
polymers and an antacid. The release inhibiting agent either fails
to have a significant effect of inhibiting the release when a
single unit of the dosage form is orally administered or has no
effect. In this way the dosage form of the present invention is
useful to deter the abuse of drugs by drug addicts or by
individuals seeking to commit suicide. In certain embodiments,
where the prescribed number of units of the immediate release of
the solid dosage form of the present invention is two, then the
composition of the release inhibiting agent used is such that the
two prescribed number of units provide the release of the drug
which is equivalent to the release obtained from the conventional,
immediate release solid dosage form. But, when three or more number
of units is tested, the release is inhibited as compared to the
equivalent number of units of the conventional immediate release
solid dosage form. It is observed that as the number of units of
the immediate release solid dosage form of the present invention
increases, release rate decreases. This will provide deterrence
particularly, against misuse, intentional such as suicidal
(overdose) or unintentional, or abuse by an abuser or addict.
[0028] The present invention provides an abuse deterrent immediate
release biphasic matrix solid dosage form that deters the abuse of
the drug by multiple pill oral administration as well as abuse by
other routes of administration such as nasal, parenteral and
rectal.
[0029] The present inventors have discovered that certain preferred
embodiments of the present invention can provide very high
resistance to multiple pill abuse. Particularly they have
discovered the preferred mode of incorporating the antacid such as
an alkalizer. When a part of the antacid is in the same phase as
the reverse enteric polymer i.e in admixture with each other, the
combination forms a highly effective release inhibiting agent. Also
particularly the present inventors have discovered release
inhibiting combination of an antacid and a reverse enteric polymer
that is soluble in acidic solutions but insoluble above second
higher pH value and insoluble above a second higher pH value is
surprisingly advantageous as compared to the reverse enteric
polymer that is soluble in acidic solutions but which swells or
gels above a second higher pH value. When multiple pills are taken
by human subjects, the dosage form of the present invention
significantly suppresses the in-vivo release and the peak plasma
levels of the drug that could arise from the ingestion of multiple
pills are significantly suppressed.
[0030] The present inventors have further discovered useful abuse
deterrent immediate release biphasic matrix solid dosage forms
capable of deterring multiple modes of abuse including:
[0031] a. intentional abuse of overdosing or multiple unit
administration by an addict or by a subject having suicidal
intention,
[0032] b. intentional abuse of extraction from multiple unit
administration by an addict or by a subject having suicidal
intention
[0033] c. unintentional or accidental overdosing,
[0034] d. concomitant alcohol consumption and resultant
drug-alcohol interaction
[0035] e. intentional abuse by nasal, parenteral, rectal or oral
route
[0036] f. separating two phases by physical means with an intention
to abuse
[0037] Particular embodiments have been discovered that
simultaneously resolve two or three or all four of the above modes
of abuse. Further embodiments of biphasic matrix solid dosage forms
have been discovered that are resistant to physical means for
separating the two phases with an intention to abuse.
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] FIG. 1 depicts an Abuse Deterrent Immediate Release biphasic
matrix solid dosage form of Biphasic matrix Type I having drug and
reverse enteric polymer in intragranular phase and antacid such as
alkalizer in the extragranular phase.
[0039] FIG. 2 depicts an Abuse Deterrent Immediate Release biphasic
matrix Solid dosage form of Biphasic matrix Type II having drug,
reverse enteric polymer and an alcohol dose-dumping resistance
polymer in the intragranular phase and antacid such as alkalizer in
the extragranular phase.
[0040] FIG. 3 depicts an Abuse Deterrent Immediate Release biphasic
matrix solid dosage form of Biphasic matrix Type III having a core
containing drug and reverse enteric polymer and a coating of
alcohol dose-dumping resistance polymer, the coated core forming an
intragranular phase and antacid such as alkalizer in the
extragranular phase.
[0041] FIG. 4 depicts an Abuse Deterrent Immediate Release biphasic
matrix solid dosage form of Biphasic matrix Type IV with drug,
reverse enteric polymer and a part of the antacid such as alkalizer
in intragranular phase and part of the antacid such as alkalizer,
in the extragranular phase.
[0042] FIG. 5 depicts an Abuse Deterrent Immediate Release biphasic
matrix solid dosage form of Biphasic matrix Type V with
intragranular phase containing drug, a part of the antacid such as
alkalizer, reverse enteric polymer and an alcohol dose-dumping
resistance polymer and a part of the antacid such as alkalizer, in
the extragranular phase.
[0043] FIG. 6 depicts an Abuse Deterrent Immediate Release biphasic
matrix solid dosage form of Biphasic Matrix Type VI with drug,
reverse enteric polymer and a part of the alkalizer and an alcohol
dose-dumping resistance polymer in intragranular phase and part of
the antacid such as alkalizer and an alcohol dose-dumping
resistance polymer, in the extragranular phase.
[0044] FIG. 7 depicts an Abuse Deterrent Immediate Release biphasic
matrix solid dosage form of Biphasic matrix Type VII, having a core
containing a drug, reverse enteric polymer, a part of the antacid
such as alkalizer and a coat containing alcohol dose-dumping
resistance polymer, the coated core forming an intragranular phase
and a part of the antacid such as alkalizer in the extragranular
phase.
[0045] FIG. 8 depicts an Abuse deterrent Immediate release biphasic
matrix solid dosage form of Biphasic matrix Type VIII having a core
containing drug, reverse enteric polymer and a part of the alcohol
dose-dumping resistance polymer; the core being coated with
remaining part of the alcohol dose-dumping resistance polymer, the
coated core forming an intragranular phase and an extragranular
phase having an antacid such as alkalizer.
[0046] FIG. 9 depicts an Abuse Deterrent Immediate Release biphasic
matrix solid dosage form of Biphasic matrix Type IX having a core
containing drug, reverse enteric polymer, a part of the antacid
such as alkalizer and an alcohol dose-dumping resistance polymer,
wherein the core is coated with alcohol dose-dumping resistance
polymer, the coated core forming the intragranular phase and an
extragranular phase containing a part of the antacid such as
alkalizer.
[0047] FIG. 10 depicts an Abuse Deterrent Immediate Release
biphasic matrix Solid dosage form of Biphasic matrix Type X having
a core containing drug, reverse enteric polymer, part of the
antacid such as alkalizer and a part of an alcohol dose-dumping
resistance polymer, the core is coated with a part of the alcohol
dose-dumping resistance polymer, the coated core forming an
intragranular phase and remaining part of the alcohol dose-dumping
resistance polymer and a part of the antacid such as alkalizer in
the extragranular phase.
[0048] FIG. 11 depicts an Abuse Deterrent Immediate Release
biphasic matrix solid dosage form of Biphasic matrix Type XI having
a core containing drug, reverse enteric polymer and an alcohol
dose-dumping resistance polymer, which is coated with alcohol
dose-dumping resistance polymer, forming an intragranular phase and
an antacid such as alkalizer and a part of the alcohol dose-dumping
resistance polymer forming an extragranular phase.
[0049] Although not shown in FIGS. 1 to 11, additional properties
in the above exemplary Types may be imparted, and particularly, for
example where required, embodiments of the solid dosage form can be
tamper or crush resistant or on crushing and other physical means
the two phases cannot be separated.
[0050] FIG. 12 is the graph of % release of the drug Vs time in
minutes for the oral dosage form of Example 1, when N units of the
dosage form are placed together in the dissolution bath to check
the dissolution release of the drug.
[0051] FIG. 13 is the graph of % release of the drug Vs time in
minutes for the oral dosage form of Example 2, when N units of the
dosage form are placed together in the dissolution bath to check
the dissolution release of the drug.
[0052] FIG. 14 is the graph of % release of the drug Vs time in
minutes for the oral dosage form of Example 3, when N units of the
dosage form are placed together in the dissolution bath to check
the dissolution release of the drug.
[0053] FIG. 15 is the graph of % release of the drug Vs time in
minutes for the oral dosage form of Example 4, when N units of the
dosage form are placed together in the dissolution bath to check
the dissolution release of the drug.
[0054] FIG. 16 is the graph of % release of the drug Vs time in
minutes for the oral dosage form of Example 5, when N units of the
dosage form are placed together in the dissolution bath to check
the dissolution release of the drug.
[0055] FIG. 17 is a graph of the % reduction in the peak plasma
level range obtained by administration of more than the prescribed
number of units of the dosage form (three) having a release
inhibiting agent according to the present invention as compared to
the peak plasma levels achieved by administration of the prescribed
number of unit of the dosage form (one) that may or may not be
devoid of any release inhibiting agent according to the present
invention. FIG. 17 shows the graph of number of subjects falling in
different % ranges of reduction in the C.sub.max.
[0056] FIG. 18 provides a X-ray diffraction pattern of (i) model
drug (Tapendadol), (ii) placebo mixture of reverse enteric polymer
and alcohol dose-dumping resistance polymer, (iii) physical mixture
of drug, reverse enteric polymer and alcohol dose-dumping
resistance polymer and (iv) milled hot-melt extrudates of drug with
reverse enteric polymer and alcohol dose-dumping resistance
polymer.
DEFINITIONS
[0057] The term `abuse` as used herein means the ingestion of the
drugs by individuals with the intention of achieving a feel of
high. The term `abuse` also covers the over-ingestion of the drug
intentionally or unintentionally. In case of intentional abuse it
may be an attempt to suicide or driven by an addiction to the drug
or in case of unintentional, it may be accidental consumption of
more number of units of the drugs than the prescribed.
[0058] The phrase `release inhibiting agent` used herein means
agent that inhibits the release of the drug. According to the
present invention, the release inhibiting agent is a combination of
one or more reverse enteric polymers and an antacid.
[0059] The term, "reverse enteric polymer" as used herein refers to
a polymer that is soluble in acidic solutions but is insoluble or
alternatively swells or gels above a second higher pH value.
Whether a polymer is insoluble above the second pH value is
determined as follows:
[0060] 500 mg of the reverse enteric polymer is dispersed in 100 ml
of 0.05 N HCL and its pH adjusted to the second pH value by adding
an alkali. Percent transmission of the dispersion is measured at
260 nm. The reverse enteric polymer is defined as `insoluble` at
and above the second specific pH value, if the percent transmission
obtained at the second pH value is below 70%.
[0061] The term `antacid` as used herein means any agent that
suppresses the gastric acid environment. The antacid may work by
physicochemical mechanisms that result in inhibition of in-vitro
release as well as in-vivo release. For example, an alkalizer can
increase the pH by neutralization of acid.
[0062] The term "granular" as used herein means an agglomerate of
multiple particles bound together physically and encompassing
granules, extrudates, pellets, pills, and the like.
[0063] The term Biphasic Matrix refers to the presence of atleast
two distinct regions or phases, one an intragranular phase and the
other an extragranular phase. The term `intra-granular phase` is
meant to include granules or agglomerates or pellets, that are
uncoated or are coated with an alcohol dose-dumping resistance
polymer, the coating being considered as a part of the
intragranular phase even though it is a coating. However, the
coatings do not include coatings containing polymers that would be
rate-controlling. For example, coating of reverse enteric polymer
may be rate controlling at pH's above 5.5.
[0064] The term `solid dispersion` as intended herein refers to a
dispersion wherein the solid state of a drug in solid diluent as
determined by X-ray diffractogram compared to a physical mixture of
the drug and solid diluent made shows that the peaks characteristic
of the crystalline drug are reduced or absent. Solid dispersions
may also be called solid-state dispersions.
[0065] The term `alcohol dose-dumping resistance polymer` refers to
polymers that are generally soluble in water but are insoluble in
40% v/v solution in water used in an amount such that they allow
immediate release of the drug in the absence of alcohol but provide
improved resistance to alcohol dose-dumping as tested by
dissolution in 40% v/v alcohol. Therefore, the term incorporates by
definition, use of appropriate amounts.
DETAILED DESCRIPTION OF THE INVENTION
[0066] The abuse deterrent immediate release biphasic matrix solid
dosage form of the present invention comprises a drug susceptible
to abuse and a release inhibiting agent wherein the release
inhibiting agent is a combination of one or more reverse enteric
polymers and an antacid wherein atleast one polymer is a reverse
enteric polymer. The second polymer may be an alcohol dose-dumping
resistance polymer. The alcohol dose-dumping resistance polymer is
used in amounts sufficient to prevent alcohol dose-dumping.
Dose-dumping resistance of the solid dosage form is tested as
illustrated in working Example 5A hereinbelow.
[0067] According to the present invention, the drug susceptible to
abuse includes, but is not limited to, opioids, central nervous
system (CNS) depressants and stimulants. The opioids are usually
prescribed to treat pain. Central nervous system depressants are
used to treat anxiety and sleep disorders and the stimulants are
most often prescribed to treat attention deficit hyperactive
disorder (ADHD). Opioids act by attaching to specific proteins
called opioid receptors, which are found in the brain, spinal cord,
gastrointestinal tract, and other organs in the body. When these
drugs attach to their receptors, they reduce the perception of
pain. Opioids can also produce drowsiness, mental confusion,
nausea, constipation, and, depending upon the amount of drug taken,
can depress respiration. Some people experience a euphoric response
to opioid medications, since these drugs also affect the brain
regions involved in reward. Those who abuse opioids may seek to
intensify their experience.
[0068] According to the present invention, the drug susceptible to
abuse may be an opioid. The opioids are selected from the group
consisting of, but are not limited to, alfentanil, allylprodine,
alphaprodine, anileridine, benzylmorphine, bezitramide,
buprenorphine, butorphanol, clonitazene, codeine, desomorphine,
dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine,
dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,
dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,
ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl,
heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,
ketobemidone, levorphanol, levophenacylmorphan, lofentanil,
meperidine, meptazinol, metazocine, methadone, metopon, morphine,
myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,
normethadone, nalorphine, normorphine, norpipanone, opium,
oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone,
phenomorphan, phenazocine, phenoperidine, piminodine, piritramide,
proheptazine, promedol, properidine, propiram, propoxyphene,
sufentanil, tapentadol, tilidine, tramadol, pharmaceutically
acceptable salts thereof, and mixtures thereof.
[0069] According to the present invention, the drug susceptible to
abuse may be central nervous system (CNS) depressants. The central
nervous system (CNS) depressants are selected from the group
consisting of, but are not limited to, alprazolam, bromazepam,
chlordiazepoxied, clorazepate, diazepam, estazolam, flurazepam,
halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam,
quazepam, temazepam, triazolam, methylphenidate, amobarbital,
aprobarbotal, butabarbital, butalbital, methohexital,
mephobarbital, metharbital, pentobarbital, phenobarbital,
secobarbital, pharmaceutically acceptable salts thereof, and
mixtures thereof. According to one embodiment of the present
invention, the drugs that cause emergency situations when taken in
overdose include, but are not limited to, opioids, central nervous
system depressants and stimulants. The opioids are usually
prescribed to treat pain. Central nervous system depressants are
used to treat anxiety and sleep disorders and the stimulants are
most often prescribed to treat attention deficit hyperactive
disorder (ADHD). Opioids act by attaching to specific proteins
called opioid receptors, which are found in the brain, spinal cord,
gastrointestinal tract, and other organs in the body. When these
drugs attach to their receptors, they reduce the perception of
pain. Opioids can also produce drowsiness, mental confusion,
nausea, constipation and depending upon the amount of drug taken,
can depress respiration. Some people experience a euphoric response
to opioid medications, since these drugs also affect the brain
regions involved in reward. Those who abuse opioids may seek to
intensify their experience.
[0070] Drugs suitable in the present invention include, but are not
limited to, drugs whose overdose consumption, can lead to emergency
visits, wherein the drugs is prescribed to be consumed by oral
administration. The drugs may be selected from the group consisting
of, but are not limited to cocaine, heroin, Cannabinoids,
Marijuana, Synthetic cannabinoids Stimulants,
3,4-methylenedioxy-N-methylamphetamine (MDMA-Ecstasy),
.gamma.-hydroxybutyric acid (GHB), Flunitrazepam (Rohypnol),
Ketamine, Lysergic acid diethylamide (LSD). It may be
psychotherapeutic agents like antidepressants-monoamio oxidase
inhibitors (MOA), phenylpiperazines like nefazodone and trazodone
or selective serotonin norepinephrine reuptake Inhibitors (SSNRI)
antidepressants like desvenlafaxine, duloxetine, venlafaxine. Other
drugs include selective serotonin Reuptake Inhibitors (SSRI)
antidepressants such as citalopram, fluoxetine, fluvoxamine,
paroxetine and sertraline. Tetracyclic antidepressants (TCA) like
maprotiline, mirtazapine, tricyclic antidepressants like
amitriptyline, desipramine, doxepin, imipramine, nortriptyline are
also suitable drugs according to the present invention. Atypical
antipsychotics like bupropion, clozapine, olanzapine, quetiapine
and risperidone, phenothiazine antipsychotics like chlorpromazine,
fluphenazine, perphenazine, prochlorperazine, thioridazine,
triflupromazine are also drugs that are suitable according to the
present invention. Other class of drugs include, analgesics,
anti-migraine agents, cyclooxygenase inhibitors, Opiates,
buprenorphine, codeine, dihydrocodeine, fenatyl, hydrocodone,
hydromorphone, mepreidine, morphine, oxycodone, pentazocine,
phenacetin, propoxyphene. Non-steroidal anti-inflammatory agents
like ibuprofen, naproxen, salicylates, aspirin, acetaminophen,
tramadol. Anorexiants like phenylpropanolamine. anticonvulsants
like barbiturates anticonvulsants, benzodiazepine anticonvulsants,
carbamate anticonvulsants, carbonic anhydrase inhibitor
anticonvulsants, dibenzazepine anticonvulsants like carbamazepine,
oxcarbazepine, rufinamide, fatty acid derivative anticonvulsants
like divalproex, sodium valproic acid, gamma-aminobutyric acid
analogs like gabapentin, hydantoin anticonvulsants like phenytoin,
oxazolidinedione anticonvulsants, pyrrolidine anticonvulsants,
succinimide anticonvulsants, triazine anticonvulsants.
Antiemetic/antivertigo agents like 5HT3 receptor antagonists,
anticholinergic antiemetics, phenothiazine antiemetics.
antiparkinson agents like anticholinergic antiparkinson agents like
benztropine, dopaminergic antiparkinsonism agents. Other drugs
include barbiturates like phenobarbital, benzodiazepines like
alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam,
flurazepam, lorazepam, oxazepam, temazepam, triazolam, misc.
anxiolytics, sedatives, and hypnotics like buspirone chloral
hydrate, diphenhydramine, doxylamine, hydroxyzine, zolpidem. CNS
stimulants like amphetamine, dextroamphetamine, benzphetamine,
dextroamphetamine, and methylphenidate. Other class of drugs
includes skeletal muscle relaxants like carisoprodol,
chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol
tizanidine. cholinergic agonists, cholinesterase inhibitors,
expectorants, selective phosphodiesterase-4 inhibitors,
antiasthmatic, antitussives, leukotriene modifiers, mast cell
stabilizers and mucolytics.
[0071] Categories of the drugs, that may be used in the present
invention, further includes, centrally acting antiadrenergic agents
like clonidine, beta-adrenergic blocking agents, beta blockers like
atenolol, propranolol, calcium channel blocking agents, diuretics,
carbonic anhydrase inhibitors, loop diuretics, potassium-sparing
diuretics thiazide and thiazide-like diuretics, renin Inhibitors,
vasopressin antagonists agents for hypertensive emergencies.
Aldosterone receptor antagonists, angiotensin converting enzyme
inhibitors, angiotensin II inhibitors and antiarrhythmic agents. It
also includes drugs like anti-infectives like ameobicides,
aminoglycosides, anthelmintics, antifungals like Azole antifungals
and echinocandins, polyenes. Antimalarial agents like quinolones.
Anti-tuberculosis agents like aminosalicylates, nicotinic acid
derivatives, rifamycin derivatives, streptomyces derivatives.
antiviral agents like adamantane antivirals, antiviral interferons,
integrase strand transfer inhibitor, Neuraminidase inhibitors,
non-nucleoside reverse-transcriptase inhibitors (NNRTIs), NRTIs,
Protease inhibitors, Purine nucleosides. Antibiotics like
carbapenems, cephalosporins, glycopeptide antibiotics
glycylcyclines, lincomycin derivatives, macrolide derivatives,
ketolides, macrolides, penicillins, aminopenicillins,
antipseudomonal penicillins, Beta-lactamase inhibitors, Natural
penicillins penicillinase resistant penicillins, quinolones,
sulfonamides, tetracyclines, and urinary anti-infective.
antineoplastics like alkylating agents, Anti-CTLA-4 monoclonal
antibodies, antimetabolites antineoplastic antibiotics,
antineoplastic hormones, antineoplastic interferons, CD20
monoclonal antibodies, EGFR inhibitors, HER2 inhibitors, histone
deacetylase inhibitors, mitotic inhibitors, mTOR inhibitors,
VEGF/VEGFR inhibitors. It also includes drugs like coagulation
modifiers like anticoagulants, coumarins and indanediones, Factor
Xa inhibitors, Heparins, Thrombin inhibitors, Antiplatelet agents,
Glycoprotein platelet inhibitors, Platelet aggregation inhibitors,
Heparin antagonists, Platelet-stimulating agents, thrombolytics.
Gastrointestinal agents like 5-aminosalicylates, Antacids,
Anti-diarrheal, digestive enzymes, functional bowel disorder
agents, chloride channel activators, peripheral opioid receptor
antagonists, Serotoninergic neuroenteric modulators, Gallstone
solubilizing agents, GI stimulants, H. pylori eradication agents,
H2 antagonists Laxatives, Proton pump inhibitors. Genitourinary
tract agents, Impotence agents, Tocolytic agents, Urinary
antispasmodics, Urinary pH modifiers, uterotonic agents. Hormones
like 5-Alpha-reductase inhibitors, adrenal cortical steroids like
corticotropin, glucocorticoids, mineralocorticoids, adrenal
corticosteroid inhibitors, antidiuretic hormones, anti-gonadotropic
agents, anti-thyroid agents, calcitonin, gonadotropin-releasing
hormone antagonists, growth hormone receptor blockers, growth
hormones, insulin-like growth factor, parathyroid hormone and
analogs, progesterone receptor modulators, prolactin inhibitors,
selective estrogen receptor modulators, sex hormones androgens and
anabolic steroids, contraceptives, Estrogens,
gonadotropin-releasing hormone and analogs gonadotropins,
progestins, sex hormone combinations, somatostatin and somatostatin
analogs, synthetic ovulation stimulants, thyroid hormones.
Immunologic agents like immune globulins, immunostimulants,
Bacterial vaccines, colony stimulating factors. interferons,
immunosuppressive agents, calcineurin inhibitors, Interleukin
inhibitors, Selective immunosuppressants, TNF alfa inhibitors
metabolic agents like antidiabetic agents, Alpha-glucosidase
inhibitors, Amylin analogs, Antidiabetic combinations like
Dipeptidyl peptidase 4 inhibitors, Insulin, meglitinides,
biguanides, sulfonylureas, thiazolidinediones, antigout agents,
antihyperlipidemic agents, antihyperlipidemic combinations. Other
classes of drugs further include bile acid sequestrants,
cholesterol absorption inhibitors, Fibric acid derivatives, HMG-CoA
reductase inhibitors, antihyperuricemic agents, bone resorption
inhibitors, bisphosphonates, glucose elevating Agents, lysosomal
enzymes, Peripherally acting antiobesity agents and miscellaneous
metabolic agents. Antipsoriatics, Antirheumatics, chelating agents,
cholinergic muscle stimulants, psoralens, smoking cessation agents.
radiologic agents like radio-contrast agents, and
radiopharmaceuticals
[0072] According to the present invention, the drugs that cause
emergency situations when taken in overdose may be central nervous
system depressants. The central nervous system depressants are
selected from the group consisting of, but are not limited to,
alprazolam, bromazepam, chlordiazepoxied, clorazepate, diazepam,
estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam,
oxazepam, prazepam, quazepam, temazepam, triazolam,
methylphenidate, amobarbital, aprobarbotal, butabarbital,
butalbital, methohexital, mephobarbital, metharbital,
pentobarbital, phenobarbital, secobarbital.
[0073] According to the present invention, the drug susceptible to
abuse may be central nervous system (CNS) stimulants. The central
nervous system (CNS) stimulants are selected from the group
consisting of, but are not limited to, amphetamines,
dextroamphetamine, methamphetamine, methylphenidate,
pharmaceutically acceptable salts thereof and mixtures thereof.
[0074] The "reverse enteric polymer" used in the solid dosage form
of the present invention is a polymer that is soluble in acidic
solutions but is insoluble or alternatively swells or gels above a
second higher pH value. In several of the embodiments, as herein
described, the reverse enteric polymer functions as a release rate
controlling polymer above a critical pH but has little rate
controlling ability below the critical pH. Examples are found in
polymers that have group capable of accepting the hydrogen ion from
an acid below the critical pH and thus becoming soluble in acid
environment and fall under the class of pH dependent polymers.
[0075] The reverse enteric polymer used is selected from polymers
that are prepared by polymerizing a mixture of the hydrophobic and
basic monomer or a mixture of the hydrophobic, hydrophilic and
basic monomer wherein the basic monomer may be selected from the
group consisting of dimethyl amino ethyl acrylate, diethyl amino
ethyl ethacrylate, diethyl amino ethyl acrylate, piperidine ethyl
methacrylate and 2-tert-butyl amino ethyl methacrylate.
[0076] An example of a preferred reverse enteric polymer i.e a pH
dependent polymer used is a methyl methacrylate butyl
methacrylate-dimethyl aminoethyl methacrylate copolymer which is a
cationic copolymer synthesized from dimethyl aminoethyl
methacrylate and neutral methacrylic acid esters, more particularly
as is commercially available under the trade name Eudragit.TM. E
which is soluble below an acidic pH such as pH 5 and swellable and
permeable above about a higher pH such as above 5.0. It is depicted
by the following structure.
##STR00001##
[0077] The repeating unit in the polymer has the following
structure: where R represents CH3 and C.sub.4H.sub.9 groups and the
polymer has a molecular weight about 1,50,000. They may exist in
different physical forms. The Eudragit.TM. E 100 product is
granular, the Eudragit.TM. E 12.5 product is a 12.5% solution of E
100 in isopropanol and acetone, and the Eudragit EPO product is a
fine powder made from E 100. Various grades of this polymer are
commercially available from Evonik, Germany. The amount of
Eudragit.TM. E in the present invention varies from 0.5% to about
30% by weight of the composition, preferably about 2% to about 30%
by weight of the composition, more preferably about 5% to about 20%
by weight of the composition. The ratio of weight of polymer to the
weight of drug varies from 0.5 to about 8.0, preferably about 3.0
to about 8.0, more preferably about 6.8. The amount of this reverse
enteric polymer may be expressed in terms of its weight ratio. The
embodiments, having biphasic matrix type i.e when the reverse
enteric polymer is in admixture with the drug, the weight ratio of
the methyl methacrylate butyl methacrylate-dimethyl aminoethyl
methacrylate copolymer to the drug susceptible to abuse, such as
tapendalol hydrochloride, a highly water soluble drug, can vary
from 4 to 15, preferably about 8. However, the ratio of methyl
methacrylate butyl methacrylate-dimethyl aminoethyl methacrylate
copolymer to the drug susceptible to abuse may vary depending upon
the solubility and the dose of the drug, present in each unit.
[0078] Other suitable examples of such pH dependent polymers may be
found in the art. It is beneficial to use polymers which are
soluble only at pH 5.5 or below, that are additionally also
impermeable since this further helps control the dissolution rate.
In more preferred embodiments of the present invention the reverse
enteric polymer is selected from a polymer that is soluble below
about pH 5 but insoluble above about pH 5.5. For example,
US20050137372 disclosed similar polymers prepared by polymerizing a
mixture of the hydrophobic and basic monomer or a mixture of the
hydrophobic, hydrophilic and basic monomer wherein the basic
monomer may be selected from the group consisting of dimethyl amino
ethyl acrylate, diethyl amino ethyl ethacrylate, diethyl amino
ethyl acrylate, piperidine ethyl methacrylate and 2-tert-butyl
amino ethyl methacrylate. Several other polymers having basic
functional groups and thus the desired pH dependent solubility
behavior can be used according to the present invention.
Poly(lysine) (PL), poly(ethylenimine) (PEI) and chitosan are
examples of such polymers.
[0079] The reverse enteric polymer used in the compositions of the
present invention may be used in the form of a dispersion or in a
powder form for preparing the compositions.
[0080] It is thus within skill in the art to use existing polymers
with the appropriate basic ionizable groups or to synthesize new
such polymers by incorporating monomers having basic ionizable
groups and any such polymer may be used according to the scope of
the present invention.
[0081] Suitable examples of the reverse enteric polymer that is
soluble at an acidic but is insoluble at a second higher pH value,
include, but are not limited to, methyl methacrylate and
diethylaminoethyl methacrylate and the like. Any other reverse
enteric polymer having such properties is encompassed within the
scope of this embodiment of the present invention. In one specific
preferred embodiment, the reverse enteric polymer that can be
utilized in the present invention is a copolymer comprising amino
and/or alkylamino and/or dialkyl amino groups such as copolymers
comprising methyl methacrylate and diethylaminoethyl methacrylate
such as commercially available as Kollicoat.RTM. Smartseal 30 D
from BASF. The polymer has a molecular weight of about 200,000 and
a glass transition temperature of 57 to 63.degree. C. The
embodiments, having biphasic matrix type i.e when the reverse
enteric polymer is in admixture with the drug, the ratio of methyl
methacrylate and diethylaminoethyl methacrylate to the drug
susceptible to abuse, such as tapendalol hydrochloride, a highly
water soluble drug, can vary from 6 to 50, preferably about 5 to
15.
[0082] Thus, in one aspect of abuse deterrent immediate release
biphasic matrix solid dosage form of the present invention
comprises a drug susceptible to abuse and a release inhibiting
agent wherein the release inhibiting agent is a combination of
polymer and an antacid wherein the antacid is an alkalizer and
further wherein atleast one polymer is a reverse enteric polymer
and functions as a release rate controlling polymer above a
specific pH but has little rate controlling ability below the
critical pH. Alternatively, the antacid may be a substance that
suppresses gastric acid secretion for example, H2-antagonist.
[0083] The term "alkalizer" as used herein refers to
physiologically acceptable substances that neutralize acid.
Examples of alkalizer include, but are not limited to calcium
carbonate, disodium hydrogen phosphate, trisodium orthophosphate,
sodium hydroxide, sodium carbonate, potassium hydroxide, sodium
bicarbonate, dipotasium carbonate, tromethamine, aluminum
trihydroxide, magnesium dihydroxide, aluminium oxide, magnesium
oxide and mixture thereof. The amount of alkalizer used in a single
unit is selected so that it will not be sufficient to raise the
stomach pH to above a critical pH for example 5 or neutral pH; but
when more than the prescribed number of units are administered, it
is sufficient to raise the pH of the stomach to above the critical
pH. Usually the amount of alkalizer in when more than the
prescribed number of units should atleast raise the pH of 500 ml of
0.01 N HCl to above the critical pH, preferably the amount should
be greater and raise the pH of 1000 ml of 0.01N HCl to above the
critical pH, and more preferably it may exceed that amount
sufficiently to neutralize any immediate rebound secretion of
acidic gastric fluids in response to the alkalizer. The amount of
alkalizer in one single unit is however selected so that it does
not raise the pH of 500 ml, preferably 1000 ml of 0.01N HCl to
above the critical pH so that when a single unit is orally
administered the polymer does not behave like a rate controlling
polymer but when more than the prescribed number of units are
administered, it behaves like a rate controlling polymer and
inhibits release.
[0084] Various embodiments according to the present invention are
categorized into various types. These will be explained in great
details hereinafter.
[0085] The solid dosage form of the present invention may include a
second polymer which is an alcohol dose-dumping resistance polymer.
These polymers may be soluble or insoluble in 100% water but are
insoluble in 40% v/v solution of alcohol in water. These polymers
may be incorporated either in intragranular phase or extragranular
phase and when used in sufficient amount provide improved
resistance to alcohol dose dumping and at the same time they do not
slow down the rate of release of the drug allowing the dosage form
to perform as an immediate release dosage form. Examples of such
polymers include, but are not limited to, ethyl cellulose,
polyvinyl alcohol, polyethylene oxide, sodium starch glycolate and
the like and mixture thereof. The polymers that do not affect or
control the release of the drug from the immediate release dosage
form are suitable to be incorporated into the abuse deterrent
immediate release solid dosage form according to the present
invention.
[0086] The solid dosage form of the present invention may be
fabricated into a suitable form such as sachets, capsules or tablet
by methods known in the art and using conventional excipients known
in the art such as diluents or fillers, binders, disintegrants,
stabilisers glidants, lubricants, surfactants, solubilizing agents,
preservatives, coloring agents and others as may be necessitated by
the drug to be incorporated in the dosage form. In one specific
embodiment, the inventors found that certain disintegrants exhibit
reduced swelling power in alcoholic solutions but show very good
swelling and disintegration effect in aqueous medium that are
devoid of alcohol. Such type of disintegrants is preferable. These
type of disintegrants, not only provide resistance to tampering by
extracting with alcohol, but help in avoiding dose dumping when the
solid dosage form is ingested with alcohol or alcoholic beverages.
Examples of such disintegrants include, but are not limited to,
sodium starch glycolate, polacrillin potassium and the like and
mixtures thereof.
[0087] Biphasic matrix solid dosage form refers to solid dosage
forms having an intragranular phase and an extragranular phase.
Intragranular phase is formed by agglomeration of particles into
granules, extrudates, pellets, mini-tablets or tablets etc.
[0088] The biphasic matrix solid dosage forms may be further sub
categorized into different types referred to as Type I, Type II,
Type III, Type IV, Type V, Type VI, Type VII, Type VIII, Type IX,
Type X, Type XI and Type XII. Each of these types is illustrated by
way of FIGS. 1 to 12.
[0089] Type I as depicted in FIG. 1 refers to an Abuse Deterrent
Immediate Release Solid dosage form of Biphasic matrix Type I
having drug and reverse enteric polymer in intragranular phase and
antacid such as alkalizer in the extragranular phase.
[0090] Type II depicted in FIG. 2 refers to an Abuse Deterrent
Immediate Release Solid dosage form of Biphasic matrix Type II
having drug, reverse enteric polymer and an alcohol dose-dumping
resistance polymer in the intragranular phase and antacid such as
alkalizer in the extragranular phase.
[0091] Type III depicted in FIG. 3 refers to an Abuse Deterrent
Immediate Release Solid dosage form of Biphasic matrix Type III
having a core containing drug and reverse enteric polymer and a
coating of alcohol dose-dumping resistance polymer, the coated core
forming an intragranular phase and antacid such as alkalizer in the
extragranular phase.
[0092] Type IV depicted in FIG. 4 refers to an Abuse Deterrent
Immediate Release Solid dosage form of Biphasic matrix Type IV with
drug, reverse enteric polymer and a part of the antacid such as
alkalizer in intragranular phase and part of the antacid such as
alkalizer, in the extragranular phase.
[0093] Type V depicted in FIG. 5 refers to an Abuse Deterrent
Immediate Release Solid dosage form of Biphasic matrix Type V with
drug, reverse enteric polymer, a part of the antacid such as
alkalizer and an alcohol dose-dumping resistance polymer in
intragranular phase and part of the antacid such as alkalizer, in
the extragranular phase.
[0094] Type VI depicted in FIG. 6 refers an Abuse Deterrent
Immediate Release Solid dosage form of Biphasic matrix Type VI with
intragranular phase containing drug, reverse enteric polymer, an
alcohol dose-dumping resistance polymer and an extragranular phase
containing an antacid such as alkalizer and an alcohol dose-dumping
resistance polymer.
[0095] Type VII depicted in FIG. 7 refers to an Abuse Deterrent
Immediate Release Solid dosage form of Biphasic matrix Type VII
having a core containing a drug, reverse enteric polymer, a part of
the antacid such as alkalizer and a coat containing alcohol
dose-dumping resistance polymer, the coated core forming an
intragranular phase and a part of the antacid such as alkalizer in
the extragranular phase.
[0096] Type VIII depicted in FIG. 8 refers to an Abuse Deterrent
Immediate Release Solid dosage form of Biphasic matrix Type VIII
having a core containing drug, reverse enteric polymer and a part
of alcohol dose-dumping resistance polymer; the core being coated
with remaining part of the alcohol dose-dumping resistance polymer,
the coated core forming an intragranular phase and an extragranular
phase having an antacid such as alkalizer.
[0097] Type IX depicted in FIG. 9 refers to an Abuse Deterrent
Immediate Release Solid dosage form of Biphasic matrix Type IX
having a core containing drug, reverse enteric polymer, a part of
the antacid such as alkalizer and an alcohol dose-dumping
resistance polymer, wherein the core is coated with alcohol
dose-dumping resistance polymer, the coated core forming the
intragranular phase and an extragranular phase containing a part of
the antacid such as alkalizer.
[0098] Type X depicted in FIG. 10 refers to an Abuse Deterrent
Immediate Release Solid dosage form of Biphasic matrix Type X
having a core containing drug, reverse enteric polymer, part of the
antacid such as alkalizer and a part of the alcohol dose-dumping
resistance polymer, the core is coated with a part of the alcohol
dose-dumping resistance polymer, the coated core forming an
intragranular phase and remaining part of the alcohol dose-dumping
resistance polymer and a part of the antacid such as alkalizer in
the extragranular phase.
[0099] Type XI depicted in FIG. 11 refers to an Abuse Deterrent
Immediate Release Solid dosage form of Biphasic matrix Type XI
having a core containing drug, reverse enteric polymer and an
alcohol dose-dumping resistance polymer, which is coated with
alcohol dose-dumping resistance polymer, forming an intragranular
phase and an antacid such as alkalizer and a part of the alcohol
dose-dumping resistance polymer forming an extragranular phase.
[0100] In certain embodiments of the abuse deterrent immediate
release dosage form comprises a drug susceptible to abuse and a
release inhibiting agent, the release inhibiting agent consisting
of a combination of atleast two polymers and an antacid wherein
atleast one first polymer is a reverse enteric polymer and atleast
one second polymer is an alcohol dose-dumping resistance polymer
wherein the reverse enteric polymer, alcohol dose-dumping
resistance polymer and the antacid are present in amounts such that
when more than the prescribed number of units, such as two or more
number of units, of the dosage form are tested for in-vitro
dissolution in 500 ml of an acidic medium such as for example,
0.01N HCl, by USP dissolution method, the release is inhibited as
compared to the immediate release of the prescribed number of
units, such as, for example, atleast 80.+-.5% of drug in a single
prescribed unit of the dosage form in one hour. In one example,
0.01 HCL with 40% ethanol by volume was used as a dissolution
medium. The in vitro dissolution was conducted in Type II, USP
apparatus, rotating at a speed of 50 rpm. Certain embodiments may
also have a polymer incorporated in a manner to provide tamper
resistance.
[0101] The reverse enteric polymer and the antacid together
function as the release inhibiting agent. The amount and the ratios
of the reverse enteric polymer to the antacid depend on the type of
matrix and the ratio can vary from 1:1 to 1:10. The amounts and
ratios can be determined as exemplified in the examples and amounts
that function to allow immediate release when only one single unit
of the dosage form are used but function as release inhibiting
agent when multiple units are used may be determined and may vary
depending on the Type of solid dosage form involved and the choice
of the reverse enteric polymer and the antacid. In embodiment of
the Biphasic matrix type where the reverse enteric polymer is only
present in the intragranular phase and the antacid only in the
extragranular phase, the ratio of the reverse enteric polymer and
drug is about 7 and the amount of antacid ranges from about 25% of
the total dosage form. It may be noted that amount of the antacid
as well as its ionization capacity determines how much the release
can be inhibited from the more than the prescribed number of units,
for instance, in this case, it was found that when a combination of
sodium bicarbonate and magnesium oxide were used, about 25% by
weight was found not to inhibit the release from 2 units, but when
more than 2 units were subjected to dissolution, the release was
inhibited. In the cases where the antacid is a combination of
sodium bicarbonate and magnesium oxide, at a concentration of about
30% by weight, the solid dosage form was found to provide
inhibition when two units were tested. In this case, therefore, the
immediate release solid dosage form can be designed to incorporate
the unit dose of the drug, in a single unit. This shows that the
immediate release dosage form of the present invention can be
altered as per the need of the number of units at which inhibition
is desired.
[0102] In one particular embodiment, the intragranular phase is
prepared by wet granulation. These granules are mixed with the
extragranular ingredients and can be converted into a tablet by
compression or the phases may be mixed and filled into hard
gelatin.
[0103] In one particular embodiment, the reverse enteric polymer is
present in admixture with the drug in an internal phase and the
antacid is present in an external phase.
[0104] According to one aspect, the present invention provides an
abuse deterrent immediate release biphasic matrix solid dosage form
comprising: a drug susceptible to abuse and a release inhibiting
agent, the release inhibiting agent consisting of a combination of
atleast two polymers and an antacid wherein atleast one first
polymer is a reverse enteric polymer and atleast one second polymer
is alcohol dose-dumping resistance polymer, wherein the reverse
enteric polymer and the antacid such as alkalizer are present in
amounts such that when more than the prescribed number of units of
the dosage form are tested for in-vitro dissolution in 500 ml, of
an acidic medium by USP dissolution method, the release is
inhibited as compared to the immediate release of drug from a
single or prescribed number of units in 2 hours when a single or
prescribed number of units, of the dosage form is tested. The
amount of reverse enteric polymer present in the current embodiment
is from about 14 to 75%. The amount of antacid present
extragranularly ranges from about 47 to 68%. The alcohol
dose-dumping resistance polymer present intragranularly can vary
from about 2 to 15%. The granules of the present embodiment are
made by hot melt extrusion technique.
[0105] In another embodiment, the reverse enteric polymer, the
alcohol dose-dumping resistance polymer and antacid are present in
admixture with the drug in the intragranular phase. The antacid
component in the present embodiment is also present in the
extragranular phase.
[0106] In this embodiment, the amount of reverse enteric polymer
can vary from about 5% to about 15%, the amount of alcohol
dose-dumping resistance polymer can vary from about 0.5% to 5%,
preferably, about 2.5%. In this embodiment the reverse enteric
polymer is present in a range of about 19 to 67% of the
intragranular phase. The alcohol dose-dumping resistance polymer is
present in a range of about 4 to 14% of the intragranular phase.
The antacid present intragranularly is in a range of about 1 to 9%
and the antacid present extragranularly is in a range of about 50%
to 55% by weight. The granules of the present embodiment are made
by the hot melt extrusion technique.
[0107] According to one specific embodiment, the abuse deterrent
immediate release solid dosage form is resistant to alcohol. That
is, the dosage form does not increase the release rate when
concomitantly administered with alcohol or alcoholic beverages and
preferably, provides reduced rate of release in alcoholic medium as
compared to non-alcoholic medium, when tested using standard in
vitro dissolution testing methods. In one embodiment dosage form
comprises a drug susceptible to abuse and a release inhibiting
agent, the release inhibiting agent consisting of a combination of
atleast two polymers and an antacid present intragranularly wherein
atleast one first polymer is a reverse enteric polymer and atleast
one second polymer is alcohol dose-dumping resistance polymer. In
this embodiment the alcohol dose-dumping resistance polymer and
antacid are also present extragranularly. The range of alcohol
isoluble polymer present intragranularly ranges from about 4 to 5%
and the alcohol dose-dumping resistance polymer present
extragranularly ranges from about 12 to 16%. The reverse enteric
polymer present in this embodiment ranges from about 19 to 20%. The
antacid present intragranularly ranges from about 2 to 3% and the
antacid present extragranularly ranges from about 32 to 49%. The
granules of the present embodiment are prepared by hot melt
extrusion and spheronization technique.
[0108] In another embodiment the dosage form comprises of a matrix
of the drug in contact with a release inhibiting agent and an
antacid present only as an intragranular phase. The release
inhibiting agent consists of a combination of atleast one first
polymer which is a reverse enteric polymer and an alcohol
dose-dumping resistance polymer. In these embodiments, the reverse
enteric polymer is present in a range of about 29 to 30% and the
antacid is present in the range of about 2 to 5%. The alcohol
dose-dumping resistance polymer of the same embodiment can vary in
amounts in the range of 7 to 8%. The granules of the present
embodiment are prepared by the hot melt extrusion technique.
[0109] It was found that incorporation of the antacid in the
intragranular phase and the extragranular phase provided various
advantages such as below:
[0110] 1. The amount of antacid in the extragranular phase that is
required to provide the multiple pill abuse resistance was
considerably lower when compared with the solid dosage form that is
devoid of an antacid in the intragranular phase, but present in the
extragranular phase.
[0111] 2. The solid dosage form according to these embodiment of
Type V, VI, VII, VIII, X, XI, were found to be resistant to abuse
by nasal route and tampering by various mediums used by abuser such
as acidic and alcoholic beverages and the like, as compared to
embodiments of Type, I, II, III, IV, IX,
[0112] According to another aspect, the present invention provides
an abuse deterrent immediate release biphasic matrix solid dosage
form comprising: [0113] a drug susceptible to abuse and a release
inhibiting agent, [0114] the release inhibiting agent consisting of
a combination of at least two polymers and an antacid wherein at
least one first polymer is a reverse enteric polymer, and at least
an alcohol dose-dumping resistance polymer, [0115] wherein the
reverse enteric polymer and the antacid are present in amounts such
that when more than two units of the dosage form are tested for
in-vitro dissolution in 500 ml, of 0.01N HCl, Type II USP apparatus
(Paddle) rotating at a speed of 50 rpm, the release is inhibited as
compared to the immediate release of drug from a single units in 2
hours when a single unit of the dosage form is tested.
[0116] In certain embodiments of the present invention, the
internal (intragranular) phase is prepared via hot melt extrusion.
When the antacid is present in the external phase and the drug is
in admixture with the reverse enteric polymer to form an internal
phase, then the amount of antacid can vary from about 15 to 60%,
preferably, 25 to 50% by weight of the solid dosage form. In
certain embodiments, the internal phase constitutes the combination
of the reverse enteric polymer and a part of the antacid and the
external phase contains other part of the antacid, then the amount
of antacid in the internal phase can vary from about 1 to 5% by
weight and the amount of antacid present in the external phase can
vary from about 10% to 40%, preferably, 25% by weight of the solid
dosage form.
[0117] The components of each composition were premixed or blended
prior to extrusion. The resulting mixture was blended and then
screened through a sieve, for eg, No. 20 (0.85 mm) US standard
sieve. The mixture was hot melt extruded to obtain an internal
phase. This internal phase was optionally, coated with a coating
composition containing a water soluble and alcohol dose-dumping
resistance polymer, such as polyvinyl alcohol, hydroxyethyl
cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl
cellulose, sodium alginate, pregelatinized starch, hydroxypropyl
starch, alginic acid, sodium carboxymethyl cellulose, sodium starch
glycolate, ethyl cellulose and like. The polyvinyl alcohol may be
present in the form of various grades such as Opadry.RTM. II clear
88 F590007: Polyvinyl alcohol, polyethylene glycol and polysorbate
80, Opadry.RTM. II clear 85 F19250: Polyvinyl alcohol, polyethylene
glycol and polysorbate 80 and talc and the like. The sodium starch
glycolate may be present in various grades but not limited to type
A low viscosity, type C high viscosity and the like.
[0118] In another embodiment, the internal phase itself contains
the drug susceptible to abuse, reverse enteric polymer, part of the
antacid such as an alkalizer, water soluble and alcohol
dose-dumping resistance polymer. The internal phase so formed is
further mixed with part of the antacid and may be converted into a
capsule filled with the mixture of internal phase and external
phase, or the mixture may be converted into a compressed
tablet.
[0119] According to one specific aspect, the present invention
provides an abuse deterrent immediate release biphasic matrix solid
dosage form comprising: [0120] a drug susceptible to abuse and a
release inhibiting agent, [0121] the release inhibiting agent
consisting of a combination of at least two polymers and an antacid
wherein at least one first polymer is a reverse enteric polymer,
and at least one second polymer is an alcohol dose-dumping
resistance polymer, [0122] wherein the reverse enteric polymer and
a part of the antacid are present in amounts such that when more
than one unit of the dosage form are tested for in-vitro
dissolution in 500 ml, of 0.01N HCl, Type II USP apparatus (Paddle)
rotating at a speed of 50 rpm, the release is inhibited as compared
to the immediate release of drug from a single units in 2 hours
when a single unit of the dosage form is tested.
[0123] According to another aspect, the present invention provides
an abuse deterrent immediate release biphasic matrix solid dosage
form comprising: [0124] a drug susceptible to abuse and a release
inhibiting agent, [0125] the release inhibiting agent consisting of
a combination of at least two polymers and an antacid wherein at
least one first polymer is a reverse enteric polymer, and at least
one second polymer is alcohol dose-dumping resistance polymer,
[0126] wherein the reverse enteric polymer and the antacid are
present in amounts such that when more than three units of the
dosage form are tested for in-vitro dissolution in 500 ml of 0.01N
HCl, Type II USP apparatus (Paddle) rotating at a speed of 50 rpm,
the release is inhibited as compared to the immediate release of
drug from a single units in 2 hours when a single unit of the
dosage form is tested.
[0127] The present invention can be said to provide a single method
for resolving multiple modes of abuse immediate release biphasic
matrix solid dosage form comprising a drug susceptible to abuse,
the multiple modes of abuse including
[0128] a. intentional abuse of overdosing or multiple unit
administration by an addict or by a subject having suicidal
intention,
[0129] b. intentional abuse of extraction from multiple unit
administration by an addict or by a subject having suicidal
intention
[0130] c. unintentional or accidental overdosing,
[0131] d. concomitant alcohol consumption and resultant
drug-alcohol interaction the method comprising: [0132] providing an
abuse deterrent immediate release solid dosage form comprising a
drug susceptible to abuse and a release inhibiting agent, [0133]
the release inhibiting agent consisting of a combination of at
least two polymers and an antacid wherein at least one first
polymer is a reverse enteric polymer, and at least one second
polymer is alcohol dose-dumping resistance polymer such that [0134]
when the prescribed dose in a single unit of the immediate release
solid dosage form is administered, the drug is released at a
desired rate for quick onset of action, however if more than one
unit of the immediate release solid dosage form are administered,
the release of the drug is suppressed; or [0135] when a single unit
of the immediate release dosage form is administered with
concomitant alcohol consumption, the drug is released at a reduced
rate as compared to the rate of release from a single unit of the
immediate release dosage form in a subject who has not consumed
alcohol; [0136] when an abuser attempts to extract the drug from
multiple units using alcohol or soft drinks, composition provides a
barrier to extraction [0137] when an abuser attempts to extract the
drug from multiple units via nasal or parental route.
[0138] The abuse deterrent immediate release solid dosage form
according to the present invention provides resistance to tampering
by either an oral, nasal or parenteral route. An abuser when
attempts to tamper the dosage form by oral route, being an
immediate release dosage form, abuser may ingest more than the
prescribed number of units with the aim of achieving high. The
inventors have demonstrated that the dosage form provides
resistance to tampering by multiple pill administration. If an
abuser intends to tamper the biphasic matrix type of embodiments of
the multiple units of the solid dosage form of the present
invention by crushing and destroying its configuration or by nasal
or parenteral means, it was surprisingly found that the dosage form
provided resistance to such abuse by not releasing the drug either
in the nasal fluids or in aqueous medium, respectively.
Particularly, resistant to such abuse are embodiments where the
drug is present as a solid solution or solid dispersion in the
intragranular phase containing the reverse enteric polymer. The
solid solution or solid dispersion of the drug with the reverse
enteric polymer may be achieved by any techniques known in the art
such as hot melt extrusion, hot melt granulation, or spray drying a
solution of the drug and reverse enteric polymer in a suitable
solvent. In one specific embodiment, a hot melt extrusion process
was employed for achieving the solid solution or solid dispersion
of drug and the reverse enteric polymer. In one specific
embodiment, the method includes steps of: (a) mixing drug, with a
reverse enteric polymer at a temperature sufficiently high to
soften or melt the polymer and to melt or dissolve the drug in the
polymer, thereby forming a dispersion or solution of drug; and (b)
allowing the dispersion or solution to cool. The molten mass may be
cooled and then sifted to desirable size and mixed with other
excipients, and converted into a solid dosage form. It is possible
to incorporate a part of the alkalizer in the dispersion or
solution formation step, wherein the drug, reverse enteric polymer
and the part of the alkalizer are present in the intragranular
phase. This phenomenon was observed when the solid dosage form was
tested for its tamper resistance in the acidic media such as citric
acid, it provided a lesser dissolution indicating that the solid
dosage form having alkalizer in the intragranular phase presents a
better control over the resistance to tampering. Incorporation of
part of the alkalizer in the intragranular phase, also creates
difficulty for the abuser to separate the drug, reverse enteric
polymer from the alkalizer, as these are agglomerated together to
form particles.
[0139] In yet another aspect, the present invention provides an
abuse deterrent immediate release biphasic matrix solid dosage form
comprising: [0140] a drug susceptible to abuse and a release
inhibiting agent, [0141] the release inhibiting agent consisting of
a combination of at least two polymers and an antacid wherein at
least one first polymer is a reverse enteric polymer, and at least
one second polymer is alcohol dose-dumping resistance polymer,
[0142] wherein the antacid is an H2 antagonist.
[0143] The present invention provides a method of achieving
deterrence to an abuse, wherein the abuse is effected by ingestion
of more than prescribed number of units of the solid dosage form,
the abuse being either intentional or unintentional. The solid
dosage form according to one of the embodiments of the present
invention was tested for pharmacokinetic parameters such as vplasma
concentration levels by orally administering more than prescribed
number of units such as three. It was found that there was a
reduction in the maximum plasma concentration (C.sub.max) when
three units of the solid dosage form were administered as compared
to the expected C.sub.max. Expected C.sub.max is the plasma level
theoretically achieved if three tablets of test product were
ingested. This shows that the immediate release biphasic matrix
solid dosage form of the present invention provides deterrence to
abuse via administration of more than the prescribed number of
units. The reduced C.sub.max would provide deterrence to the abuser
who attempts to abuse the active ingredient and achieve `high` by
taking more than prescribed number of units of the solid dosage
form concurrently.
[0144] While the present invention is disclosed generally above,
additional aspects are further discussed and illustrated with
reference to the examples below. However, the examples are
presented merely to illustrate the invention and should not be
considered as limitations thereto.
Examples 1 to 5
TABLE-US-00001 [0145] TABLE 1 Immediate release biphasic matrix
solid dosage form of Example 1-5 Examples Ingredient 1 2 3 4 5
Quantity mg/Tablet Intragranular Tapentadol HCl 17.40 17.40 17.40
11.60 11.60 phase Methyl methacrylate butyl 120.0 120.0 120.0 80.0
80.0 methacrylate- dimethylaminoethyl methacrylate copolymer
(Eudragit .RTM. E PO) Hydroxypropyl methyl -- -- -- 16.0 --
cellulose Granules of Polyvinyl alcohol* -- -- -- -- 16.0.sup.2
second drug Polyvinyl alcohol** -- -- -- 6.8.sup.1 -- Acetaminophen
-- -- -- 325.0 325.0 Polyethylene glycol 400 -- -- -- 5.0 --
Microcrystalline cellulose -- -- -- 47.0 47.0 Pregelatinized starch
-- -- -- 25.0 25.0 Sodium starch glycolate -- -- -- 15.0 15.0
Polyvinyl pyrrolidone -- -- -- 8.0 8.0 Extragranular Sodium
bicarbonate 560.0 560.0 280.0 280.0 280.0 Magnesium oxide -- --
50.0 50.0 50.0 Silicified Microcrystalline 298.0 293.0 293.0 149.6
161.4 cellulose Crospovidone 30.00 30.0 30.0 -- -- Talc 7.30 7.30
7.30 -- -- Magnesium Stearate 7.30 7.30 7.30 6.0 6.0 Quantity % w/w
Intragranular Tapentadol HCl 1.67 1.68 2.16 1.13 1.13 phase Methyl
methacrylate butyl 11.53 11.59 14.9 7.8 7.80 methacrylate-
dimethylaminoethyl methacrylate copolymer (Eudragit .RTM. E PO)
Hydroxypropyl methyl -- -- -- 1.56 -- cellulose Granules of
Polyvinyl alcohol* -- -- -- -- 1.6.sup.2 second drug Polyvinyl
alcohol** -- -- -- 0.66.sup.1 -- Acetaminophen -- -- -- 31.7 31.7
Polyethylene glycol 400 -- -- -- 0.48 -- Microcrystalline cellulose
-- -- -- 4.58 4.6 Pregelatinized starch -- -- -- 2.43 2.4 Sodium
starch glycolate -- -- -- 1.46 1.5 Polyvinyl pyrrolidone -- -- --
0.78 0.8 Extragranular Sodium bicarbonate 53.84 54.1 34.8 27.3 27.3
phase Magnesium oxide -- -- 6.21 4.87 4.9 Silicified
Microcrystalline 28.65 28.3 36.4 14.6 15.7 cellulose Crospovidone
2.88 2.89 3.7 -- -- Talc 0.70 0.70 0.9 -- -- Magnesium Stearate
0.70 0.70 0.9 0.58 0.58 *Opadry .RTM. II clear 88 F590007:
Polyvinyl alcohol, polyethylene glycol and polysorbate 80 **Opadry
.RTM. II clear 85 F19250: Polyvinyl alcohol, polyethylene glycol
and polysorbate 80 and talc .sup.1polyvinyl alcohol is present in
the form of coating in the drug reverse enteric polymer granules
.sup.2polyvinyl alcohol is present in the form of admixture in the
drug reverse enteric polymer granules
[0146] Examples 1-3 were prepared as follows:
[0147] Tapentadol hydrogen chloride, representing a drug
susceptible to abuse and methyl methacrylate butyl
methacrylate-dimethyl aminoethyl methacrylate copolymer
(Eudragit.RTM. EPO) and other intragranular excipients were sifted
through 30 # sieve. The mixture was extruded and the extrudates
milled and shifted through #20 to obtain granule. The granules were
blended with extragranular excipients and subjected to compression
using suitable shaped punches to obtain tablets.
[0148] Example 4 was prepared as follows:
[0149] Tapentadol hydrogen chloride, Methyl methacrylate butyl
methacrylate-dimethylaminoethyl methacrylate copolymer
(Eudragit.RTM. EPO), Hypromellose (Methocel.RTM. E-5 LV premium)
and Polyethylene glycol 4000 were sifted through 30 # and mixed.
The mixture was extruded in a hot melt extruder. Extrudates so
obtained were milled and shifted through 20 # sieve. Coating
dispersion was prepared by the addition of Opadry II clear 85F19250
in the vortex of purified water with stirring for 45 minutes. Then
milled extrudes were coated with n in Glatt coating machine with
top spray setup to obtain the coated Tapentadol HCl extrudates.
[0150] Acetaminophen, Microcrystalline cellulose (Avicel.RTM. PH
101), pregelatinized starch (LYCATAB-PGS.RTM.) and Sodium Starch
Glycolate (Explotab) were co-sifted through suitable mesh. Then
sifted material was transferred to Rapid mixer granulator and dry
mixed for 10 minutes with suitable impeller and chopper setting.
Binder solution was prepared by adding Povidone (Plasdone.RTM.
K-29/32) to the vortex of suitable quantity of purified water under
stirring. Granules were prepared with the dry mixed materials and
the binder solution, in a rapid mixer granulator suitable impeller
and chopper setting. Then wet granules were milled in clit mill
with suitable screen. The wet milled granules were dried in fluid
bed drier at suitable temperature. Then dried granules were milled
in clit mill with suitable screen and sift the milled granules
through suitable mesh to obtain the Acetaminophen granules.
[0151] The coated Tapentadol HCl extrudates were mixed with
Acetaminophen granules, sodium bicarbonate, magnesium Oxide and
silicified microcrystalline cellulose. It was then blended in a
suitable blender followed by lubrication with Magnesium stearate.
Then the blend was compressed to obtain tablets using suitable
shaped punches.
[0152] Example 5 was prepared as follows:
[0153] Tapentadol hydrogen chloride, Methyl methacrylate butyl
methacrylate-dimethylaminoethyl methacrylate copolymer
(Eudragit.RTM. EPO) and Opardy.RTM. II clear 88 F590007 were sifted
through suitable sieve and mixed The mixture was extruded in a hot
melt extruder and the extrudates were milled and shifted through
suitable sieve to obtain Tapentadol extrudates.
[0154] Acetaminophen, Microcrystalline cellulose (Avicel.RTM. PH
101), Pregelatinized starch (LYCATAB-PGS.RTM.) and Sodium Starch
Glycolate (Explotab) were co-sifted through suitable mesh. Then
sifted material was transferred to Rapid mixer granulator and dry
mixed for 10 minutes with suitable impeller and chopper setting.
Binder solution was prepared by adding Povidone (Plasdone.RTM.
K-29/32) to the vortex of suitable quantity of purified water under
stirring. Granules were prepared with the dry mixed materials and
the binder solution, in a rapid mixer granulator at suitable
impeller and chopper setting. The wet granules were milled in clit
mill with suitable screen. The wet milled granules were dried in
fluid bed drier at suitable temperature. Then dried granules were
milled in clit mill with suitable screen and sift the milled
granules through suitable mesh.
[0155] Tapentadol extrudates, Acetaminophen granules, Sodium
bicarbonate, Magnesium Oxide and Silicified Microcrystalline
cellulose were blended in a suitable blender followed by
lubrication with Magnesium stearate. Then blend was compressed to
obtain tablets using suitable shaped punches.
[0156] The tablets of Examples 1-5 were tested for in-vitro
dissolution in 500 ml, 0.01N HCl, in Type II USP apparatus (Paddle)
rotating at a speed of 50 rpm. Single as well as more than single
unit were placed together in the dissolution bath to check the
dissolution release of the drug. The results are shown in Table 2
and in FIGS. 1-5.
TABLE-US-00002 TABLE 2 In vitro release of `N` number of units of
Examples 1-5 % drug released Example Example Example Example 1 2 3
4 Example 5 Time N = 1 N = 2 N = 3 N = 5 N = 7 N = 1 N = 3 N = 1 N
= 3 N = 1 N = 3 N = 1 N = 3 (Min) (A)* (B*) (B*) (B*) (B*) (A)*
(B*) (A)* (B*) (A)* (B*) (A)* (B*) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 10
99 64 42 33 23 99 45 71 40 75 38 64 35 20 103 70 46 36 27 104 52 86
46 89 45 96 45 30 106 74 50 41 34 105 55 90 48 92 49 96 50 45 106
76 52 42 35 104 56 93 49 95 52 98 56 60 106 77 52 42 37 105 57 93
50 95 54 100 59 *A = % release when N = 1
[0157] It was found that the release inhibiting agent function to
release the drug rapidly in gastric fluids when a single unit is
tested but inhibited the release of the drug in gastric fluids when
more than the prescribed number of units of the dosage form were
tested.
[0158] The percent inhibition of release was calculated as
follows:
*% inhibition of release with N units=(A-B/A).times.100 where
[0159] A=% release when N=1 and B=% release with N units
[0160] The % inhibition of release with N units for examples 1 to 5
is shown in Table 3.
TABLE-US-00003 TABLE 3 Percent inhibition of release by Examples
1-5 % inhibition of release with N units* Ex- Ex- Ex- Ex- Time
Example 1 ample 2 ample 3 ample 4 ample 5 (Min) N = 2 N = 3 N = 5 N
= 7 N = 3 N = 3 N = 3 N = 3 10 35 57 67 77 55 44 49 45 20 32 55 65
74 50 47 49 53 30 30 52 61 68 48 47 47 48 45 28 51 60 67 46 47 45
43 60 27 51 60 65 46 46 43 41
[0161] These examples illustrated the abuse deterrent immediate
release solid dosage form of the present invention comprising a
drug susceptible to abuse and a release inhibiting agent wherein
the release inhibiting agent is a combination of polymer and an
alkalizer and wherein the polymer functions as a release rate
controlling polymer above a critical pH but has little rate
controlling ability below the critical pH and is present in
admixture with the drug in one phase and the alkalizer is present
in another phase (biphasic matrix type). Thus it was observed that
when two or more units of the biphasic matrix type embodiments of
the present invention were orally administered, the release was
inhibited as compared to the release when a single unit of the
dosage form was orally administered.
[0162] In the particular, in the illustrative examples 1-5, the
percent inhibition observed was from about 30% to about 80% at 10,
20, 30, 45 and 60 minutes. When N was 2, the percent inhibition in
the illustrative example was from about 30 to 35%. The percent
inhibition ranged from about 40 to about 60%, when N was 3, from
about 60 to 70% when N was 5 and from about 65 to about 80% when N
was 7.
[0163] As dosage forms intended for quick onset of action are given
a number of times a day as compared to slow release forms that are
given at a lower frequency for example once-a-day, they contain a
lower amount of drug than in the extended release form. An abuser
will want to receive higher amounts by taking multiple pills.
Therefore, the percent of prescribed dose that an abuser will
release at 10 min. and 60 min. for absorption by taking multiple
units of the dosage form was calculated. The prescribed dose is the
amount contained in a single unit of the dosage form. Table 4 shows
the results for Examples 1-5.
TABLE-US-00004 TABLE 4 Estimated percent prescribed dose release at
10 minutes and 60 minutes upon abuse by multiple unit
administration of the biphasic matrix type dosage form of the
present invention D.sub.10* D.sub.60** Examples N = 1 N = 2 N = 3 N
= 5 N = 7 N = 1 N = 2 N = 3 N = 5 N = 7 1 99 128 126 165 161 106
154 156 210 259 2 99 -- 135 -- -- 105 -- 171 -- -- 3 71 -- 120 --
-- 93 -- 150 -- -- 4 75 -- 76 -- -- 95 -- 162 -- -- 5 64 -- 70 --
-- 100 -- 177 -- -- *D.sub.10 = Percent prescribed dose released in
10 minutes = (Total amount released/amount in prescribed number of
units of the dosage form) .times. 100 **D.sub.60 = Percent
prescribed dose released in 60 minutes = (Total amount
released/amount in prescribed number of units of the dosage form)
.times. 100
Example 5A
[0164] Example 5A demonstrates the ability of the immediate release
solid dosage form to provide resistance to drug release in presence
of alcohol.
[0165] This embodiment provides the solid dosage form that is
alcohol resistant. Immediate release solid dosage forms according
to the Example 4 and Example 5 were tested for the in vitro
dissolution in the presence and absence of alcohol. The tablets
were tested for in-vitro dissolution in 500 ml, 40% v/v ethanolic
solution, in Type II USP apparatus (Paddle) rotating at a speed of
50 rpm.
[0166] Example 4 and Example 5 represent the embodiment of the
present invention wherein the abuse deterrent immediate release
solid dosage form comprises a drug susceptible to abuse and a
release inhibiting agent, the release inhibiting agent consisting
of a combination of a reverse enteric polymer and an alcohol
dose-dumping resistance polymer.
[0167] The following data shows that when a single unit of the
immediate release dosage form is administered with concomitant
alcohol consumption, the drug is released at a reduced rate as
compared to the rate of release from a single unit of the immediate
release dosage form in a subject who has not consumed alcohol.
TABLE-US-00005 TABLE NO. 5 Results of the In vitro release of the
drug from the single unit of the dosage form in the presence and
absence of 40% ethanolic medium Example 1 Example 4 Example 5 (N =
1) (N = 1) (N = 1) Dissolution medium Time in with 40% without with
40% without with 40% without minutes alcohol alcohol alcohol
alcohol alcohol alcohol 10 68 0 22 75 22 64 20 85 99 41 89 39 96 30
94 103 53 92 49 96 45 96 106 70 95 59 98 60 100 106 77 95 64
100
[0168] The results in the above table indicate that when an abuser
attempts to extract the drug from multiple units using alcohol or a
user unintentionally takes substantial quantity of alcohol, the
composition provides a barrier to extraction or to alcohol
dose-dumping.
Example 5B
[0169] Example 5B demonstrates the ability of the immediate release
solid dosage form to provide resistance to extraction by use of
acidic beverages that may be used by an abuser.
[0170] Solid dosage form of the Example 5 represents an embodiment
of the present invention wherein the abuse deterrent immediate
release solid dosage form comprises: a drug susceptible to abuse
and a release inhibiting agent, the release inhibiting agent
consisting of a combination of a reverse enteric polymer and
alcohol dose-dumping resistance polymer such as polyvinyl alcohol
and antacid. The Solid dosage form of Example 5 was evaluated for
ability to resist the abuse by techniques such as extraction of the
drug using acidic beverages such as soft drinks like, for eg. Coca
Cola.RTM. and Sprite.RTM.. In order to evaluate this, multiple
units of the solid dosage form were subjected to in vitro release
in 500 ml of the soft drink and the release was measured for 1
hour.
TABLE-US-00006 TABLE NO. 6 Results of Evaluation of the ability of
the immediate release solid dosage form of Example 5 (Five units)
to provide resistance to extraction by soft drinks by an abuser %
In vitro dissolution of Five Immediate Time in release solid dosage
form of Example 5 minutes Coca cola .RTM. Sprite .RTM. 5 32 49 10
40 64 15 44 69 30 48 75 45 51 76 60 53 77
[0171] The results from EXAMPLE 5A and EXAMPLE 5B illustrate that
when an abuser attempts to extract the drug from multiple units of
the immediate release solid dosage form of the present invention
using alcohol or soft drinks, dosage form shows ability to provide
a barrier to extraction.
Example 6 and Example 6 A
TABLE-US-00007 [0172] TABLE 7 Immediate release solid dosage form
of Example 6 and Example 6A Descrip- tion of Example 6 Example 6 A
the dosage Mg per % by Mg per % by form Ingredients tablet weight
tablet weight Drug model drug 11.60 1.45 11.60 1.70 `reverse
(Tapentadol HCl) enteric Methyl methacrylate 80.00 10.0 80.00 11.76
polymer` butyl methacrylate- granules dimethylaminoethyl
methacrylate copolymer Polyvinyl alcohol** 16.00 2.0 16.00 2.35
Magnesium -- -- 10.00 1.47 Oxide: base Extra- Sodium bicarbonate
280.00 35.0 280.00 41.17 granular Magnesium Oxide 50.00 6.25 -- --
Silicified 269.9 33.7 228.4 33.58 Microcrystalline cellulose
Crospovidone 70.00 8.75 40.00 6.88 Colloidal Silicon 8.50 1.06 --
Dioxide Talc 7.00 0.87 7.00 1.02 Magnesium Stearate 7.00 0.87 7.00
1.02 **Opadry .RTM. II Clear 88F590007: polyvinyl alcohol;
[0173] The extrudates were prepared by hot melt extrusion. All the
ingredients of the hot melt extrusion stage were sifted through a
suitable sieve. The sifted ingredients were mixed and extrudates
were prepared using hot melt extruder. The extrudates were milled
and sifted through sieve. The extrudates were lubricated and
further dry mixed with sodium bicarbonate, magnesium oxide,
silicified microcrystalline cellulose, crospovidone and the mixture
is compressed into tablet.
[0174] The single and multiple units of the solid dosage form of
Example 6 and Example 6A were subjected to in vitro dissolution to
evaluate ability of the solid dosage form to provide multiple pill
abuse. For this, single and three tablets were placed in the
dissolution vessel having 500 ml 0.01 N HCL. Type II USP
dissolution apparatus rotating at a speed of about 50 rpm, was
used. The dissolution was measured for 60 minutes. Following table
provides the results of the dissolution test.
TABLE-US-00008 TABLE NO. 8 Results of the in-vitro release of the
drug from the single and three units of the dosage form of Example
6 and Example 6A Time in Example 6 Example 6 A minutes N = 1 N = 3
N = 1 N = 3 5 52 38 40 32 10 74 45 52 36 15 85 50 61 41 30 92 58 82
49 45 94 61 91 54 60 94 63 95 57
[0175] It can be seen that the reverse enteric polymer, Methyl
methacrylate butyl methacrylate-dimethylaminoethyl methacrylate
copolymer and the antacid, which is a mixture of magnesium oxide
and sodium bicarbonate, are present in amounts such that when two
or more units of the dosage form are tested for in-vitro
dissolution in 500 ml, 0.01N HCl, in Type II USP apparatus (Paddle)
rotating at a speed of 50 rpm, the release is inhibited as compared
to the immediate release of atleast 80.+-.5% of drug in a single
unit of the dosage form in 1 hour when a single unit of the dosage
form is tested.
Example 6B
TABLE-US-00009 [0176] TABLE 9 Immediate release solid dosage form
of Example 6B % by weight Ingredients mg/Tab of tab Intragranular
Tizanidine hydrochloride 2.3 0.27 phase Lactitol monohydrate 12.3
1.45 Aminomethacrylate copolymer 100. 11.76 (Eudragit .RTM. E PO)
Polyvinyl alcohol** 20. 2.35 Hydrochloric Acid 1.4 0.2
Extragranular Sodium bicarbonate Powder 280.0 32.9 phase Magnesium
Oxide Light 50. 5.9 Silicified Microcrystalline cellulose 291.5
34.3 (Prosolv SMCC 90) Crospovidone 70.0 8.2 Colloidal Silicon
Dioxide 8.5 1 Lubrication stage Talc 7.0 0.82 Magnesium Stearate
7.0 0.82 **Opadry .RTM. II Clear 88F590007-Polyvinyl alcohol,
polyethylene glycol and polysorbate 80.
Example 6B was prepared as follows:
[0177] Drug susceptible to alcohol and Lactitol monohydrate salt
were sifted, mixed and further granulated with hydrochloric acid.
The aminomethacrylate copolymer and polyvinyl alcohol were sieved
and mixed with the granulation blend prepared before. This mixture
was then extruded by hot melt extrusion. The extrudes were further
milled and mixed with sodium bicarbonate powder, magnesium oxide
light, silicified microcrystalline cellulose, crospovidone and
colloidal silicon dioxide, talc and magnesium stearate and tablets
were compressed.
[0178] Dissolution was carried out in 500 ml of 0.01N HCl in a
Type-II, USP apparatus at a rotating speed of 50 rpm in a peak
vessel. Abuse deterrence was compared by checking the decrease in
the percentage release of the drug from one unit of the solid
dosage form compared to more than the prescribed number of units
for eg 3 units. The results of the dissolution study are given
below:
TABLE-US-00010 TABLE 10 In vitro dissolution of the solid dosage
form of Example 6B % Drug Release [Mean] Number of Number of Time
in units tested units tested minutes N = 1 N = 3 5 33 12 10 63 21
15 81 29 20 90 36 30 97 46 45 98 58 60 99 65
[0179] The tablets prepared according to this example, were
subjected to pharmacokinetic study. The details of the study and
the results are provided in Example 18.
Example 7 and Example 8
TABLE-US-00011 [0180] TABLE 11 Immediate release solid dosage form
of Example 7 & Example 8 Descrip- tion of Example 7 Example 8
dosage mg per % by mg per % by form Ingredients tablet weight
tablet weight Intra- model drug 11.6 1.1 11.6 1.11 granular
(Tapentadol HCl) phase Methyl Methacrylate 80.0 7.47 100.0 9.61 and
Diethylaminoethyl Methacrylate copoly- mer dispersion * Polyvinyl
alcohol** 16.00 1.49 25.0 2.40 Tartaric acid -- -- 2.2 0.21
Magnesium Oxide -- -- 10.0 0.96 Granules Acetaminophen 420.00 39.25
NA -- of second granules drug Acetaminophen NA -- 360.0 34.61
granules (Compresso PAP .RTM. 90CPF) extra- Sodium bicarbonate
280.0 26.2 280.0 26.92 granular Magnesium Oxide 50.0 4.7 NA --
Silicified Micro- 168.4 15.74 207.2 19.92 crystalline cellulose
(Prosolv SMCC 90) Crospovidone 20.0 1.86 20.0 1.9 Silicon dioxide
10.0 0.93 10.0 0.9 Talc 7.0 0.65 7.0 0.7 Magnesium Stearate 7.0
0.65 7.0 0.7 * Methyl Methacrylate and Diethylaminoethyl
Methacrylate copolymer dispersion (Kollicoat .RTM. Smart Seal 30D)
in dried form **Polyvinyl alcohol: Opadry .RTM. II clear 85
F59007
[0181] The ingredients namely, tapentadol, Methyl Methacrylate and
diethylaminoethyl methacrylate copolymer, polyvinyl alcohol,
tartaric acid and magnesium oxide (in case of Example 8) were
sifted and mixed. The blend was subjected to hot melt extrusion to
prepare the extrudates. The extrudates were milled and sifted and
mixed with the acetaminophen granules, sodium bicarbonate,
magnesium oxide, silicified microcrystalline cellulose,
crospovidone, pregelatinized starch. They were lubricated with talc
and magnesium stearate and compressed into tablets.
[0182] The tablets of Example 7 and Example 8 were subjected to in
vitro dissolution in 500 ml of 0.01 N HCL using type II apparatus
at a rotating speed of 50 rpm. Below are the results:
TABLE-US-00012 TABLE 12 Results of in vitro release of the drug
from the single and three units of the dosage form of Example 7 and
Example 8 Time in EXAMPLE 7 EXAMPLE 8 minutes N = 1 N = 3 N = 1 N =
3 5 41 29 26 9 10 60 41 36 16 15 74 48 45 20 30 90 57 64 31 45 95
61 73 37 60 97 64 81 40
[0183] The tablets of Example 7 and example 8, were further
subjected to in vitro dissolution using 500 ml of 0.01N HCl with
720 mg citric acid using type II USP apparatus at a rotating speed
of 50 rpm. Below are the results.
TABLE-US-00013 TABLE 13 Results of the In vitro release of the drug
from three units of the dosage form in 500 ml of 0.01N HCl with 720
mg citric acid Time in EXAMPLE 7 EXAMPLE 8 minutes N = 3 N = 3 5 27
19 10 44 29 20 52 36 30 73 48 45 85 56 60 89 63
Example 9 and Example 10
TABLE-US-00014 [0184] TABLE 14 Immediate release solid dosage form
of Example 9 and 10 Descrip- tion of Example 9 Example 10 dosage mg
per % by mg per % by form Ingredients tablet weight tablet weight
Drug model drug 11.6 1.1 11.60 1.06 `reverse (Tapentadol HCl)
enteric Methyl Methacrylate 100.0 9.2 100.0 9.17 polymer` and
Diethylaminoethyl granule Methacrylate copoly- mer dispersion *
Polyvinyl alcohol** 25 2.3 25.0 2.29 Tartaric acid 2.2 0.2 2.22
0.20 Magnesium Oxide 10.0 0.9 10.00 0.91 Granules Acetaminophen 360
33.0 360 33.0 of second granules drug extra- Sodium bicarbonate 280
25.7 280 25.7 granular Polyethylene oxide 90 8.2 90 8.25 Silicified
Micro- 97.2 8.9 97.2 8.91 crystalline cellulose Crospovidone 20 1.8
20 1.83 Sodium starch 70 6.4 NA -- glycolate-Type A Sodium starch
NA -- 70 6.42 glycolate-Type C Light anyhydrous 10 0.91 10 0.91
silicic acid Talc 7 0.64 7 0.64 Magnesium Stearate 7 0.64 7 0.64 *
Methyl Methacrylate and Diethylaminoethyl Methacrylate copolymer
dispersion (Kollicoat .RTM. Smart Seal 30D) in dried form
**Polyvinyl alcohol: Opadry .RTM. II clear 85 F59007
[0185] The ingredients namely, tapentadol, Methyl Methacrylate and
diethylaminoethyl methacrylate copolymer, polyvinyl alcohol,
tartaric acid and magnesium oxide (in case of Example 10) were
sifted and mixed. The blend was subjected to hot melt extrusion to
prepare the extrudates. The extrudates were milled and sifted
through suitable sieve. The extrudates were mixed with the
acetaminophen granules, sodium bicarbonate, magnesium oxide,
silicified microcrystalline cellulose, crospovidone, pregelatinized
starch. Lubricated with talc and magnesium stearate and compressed
into tablets. The tablets of Example 10A and Example 10 B were
subjected to in vitro dissolution in 500 ml of 0.01 N HCL using
type II apparatus at a rotating speed of 50 rpm. Below are the
results:
TABLE-US-00015 TABLE 15 Results of in vitro release of the drug
from the single and three units of the dosage form of Example 9 and
Example 10 Time in EXAMPLE 9 EXAMPLE 10 minutes N = 1 N = 3 N = 1 N
= 3 5 22 11 21 11 10 34 16 34 19 15 45 22 47 21 30 68 34 71 31 45
81 40 82 38 60 90 44 88 42
[0186] The tablets of Example 10A and example 10 B, were further
subjected to in vitro dissolution using 500 ml of 0.01N HCl with
40% alcohol using type II USP apparatus at a rotating speed of 50
rpm. Below are the results.
TABLE-US-00016 TABLE 16 Results of the In vitro release of the drug
from three units of the dosage form in 500 ml of 0.01N HCl with 40%
v/v alcohol Time in EXAMPLE 9 EXAMPLE 10 minutes N = 1 N = 3 N = 1
N = 3 5 18 12 8 9 10 30 21 15 16 15 40 29 21 22 30 60 43 31 31 45
71 52 38 38 60 77 58 42 42
[0187] The tablets of the Example 9 were subjected to mechanical
tampering. The mechanical tampering was performed by grinding the
tablets into a coffee grinder for 20 seconds. The grinding
converted the tablet into powder. The powder was subjected to in
vitro dissolution in 0.01 N HCL. The results are given below:
TABLE-US-00017 TABLE 17 Results of the In vitro release of the drug
from three units of the dosage form in 500 ml of 0.01N HCl of
intact vs crushed tablets Example 9 Sample Type Intact Tablets
Crushed Tablets Time in % Drug Release minutes N = 1 N = 3 N = 3 5
22 11 15 10 34 16 22 15 45 22 28 30 68 34 40 45 81 40 48 60 90 44
53
[0188] It can be seen that in-vitro release of three tablets was
suppressed when the tablets were crushed, when compared to in-vitro
release of three intact tablets. It is found that although the
physical integrity of the tablets is made to lose, the abuse
deterrent immediate release solid dosage form of the present
invention provided resistance to tampering or misuse.
Example 11
TABLE-US-00018 [0189] Example 11 Description of mg per % by dosage
form Ingredients tablet weight Intragranular model drug 11.6 1.2
phase (Tapentadol HCl) Methyl Methacrylate 100.0 10.3 and
Diethylaminoethyl Methacrylate copolymer dispersion * Ethyl
Cellulose** 25 2.5 Tartaric acid 2.2 0.22 Magnesium Oxide 10.0 1.0
Acetaminophen granules) 360 37.1 Extragranular Sodium bicarbonate
100 10.3 phase Magnesium oxide 50 5.15 Polyethylene oxide 90.0 9.27
Silicified Micro- 107.2 11.0 crystalline cellulose Crospovidone 20
2.06 Sodium starch glycolate- 70 7.2 Type A Light anyhydrous 10 1.0
silicic acid Talc 7 0.7 Magnesium Stearate 7 0.7 (Kollicoat .RTM.
Smart Seal 30D) = * Methyl Methacrylate and Diethylaminoethyl
Methacrylate copolymer dispersion
[0190] The ingredients namely, tapentadol, Methyl Methacrylate and
diethylaminoethyl methacrylate copolymer, polyvinyl alcohol,
tartaric acid and magnesium oxide (in case of Example 10) were
sifted and mixed. The blend was subjected to hot melt extrusion to
prepare the extrudates. The extrudates were milled and sifted
through suitable sieve. The extrudates were mixed with the
acetaminophen granules, sodium bicarbonate, magnesium oxide,
silicified microcrystalline cellulose, crospovidone, pregelatinized
starch. Lubricated with talc and magnesium stearate and compressed
into tablets.
[0191] The tablets of Example 11 were subjected to in vitro
dissolution in 500 ml of 0.01 N HCL using type II apparatus at a
rotating speed of 50 rpm. Below are the results:
TABLE-US-00019 TABLE 19 Results of in vitro release of the drug
from the single and three units of the dosage form of Example 11
Time in EXAMPLE 11 minutes N = 1 N = 3 5 20 4 10 30 5 15 38 6 30 52
7 45 63 8 60 70 8
Example 12-Example 13
TABLE-US-00020 [0192] TABLE 20 Immediate Release solid Dosage form
of Example 12 and Example 13 Descrip- Ingredients tion of EXAMPLE
12 EXAMPLE 13 dosage % by % by form Ingredients mg/Tab weight
mg/Tab weight Intra- model drug 11.60 1.11 11.60 1.11 granular
(Tapentadol HCl) phase Methyl methacrylate 100.00 9.61 NA -- butyl
methacrylate- dimethylaminoethyl methacrylate co- polymer Methyl
Methacrylate NA -- 100.00 9.61 and Diethylaminoethyl Methacrylate
co- polymer dispersion Polyvinyl alcohol 25.00 2.40 25.00 2.40
Tartaric acid 2.22 0.21 2.22 0.21 Magnesium Oxide 15.00 1.44 10.00
0.96 Granules Acetaminophen 360.00 34.61 360.00 34.61 of second
granules drug Extra- Sodium bicarbonate 280.00 26.92 280.00 26.92
granular Silicified Micro- 202.2 19.44 207.2 19.9 crystalline
cellulose Crospovidone 20.00 1.92 20.00 1.92 Colloidal silicon
10.00 0.96 10.00 0.96 dioxide Talc 7.00 0.67 7.00 0.67 Magnesium
Stearate 7.00 0.67 7.00 0.67
[0193] The ingredients listed in the hot melt extrusion stage were
sifted through suitable sieve. The sifted ingredients were mixed
and subjected to hot melt extrusion. The extrudates prepared were
sifted through suitable sieve. The sieved granules/extrudates were
dry mixed in a suitable blender followed by lubrication with
ingredients of lubrication stage. The lubricated granules were
compressed into tablets.
[0194] The tablets of Example 12 and Example 13 were subjected to
in vitro dissolution in 500 ml of 0.01N HCl using Type II, USP
apparatus (Paddle) rotating at a speed of 50 rpm. The results of
the % drug released in tabulated below:
TABLE-US-00021 TABLE 21 Results of the In vitro release of the drug
from one and three units of the dosage form in 500 ml of 0.01N HCl
Time in Example 12 Example 13 minutes N = 1 N = 3 N = 1 N = 3 5 32
15 26 9 10 45 22 36 16 15 56 27 45 20 30 78 38 64 31 45 90 44 73 37
60 97 50 81 40
[0195] The results in the above table indicate that when the
prescribed dose in a single unit of the immediate release solid
dosage form is administered, the drug is released at a desired rate
for quick onset of action, however if more than one unit of the
immediate release solid dosage form are administered, the rate of
release of the drug is inhibited.
[0196] The tablets of Example 12 and Example 13 were subjected to
in vitro dissolution in 500 ml of 0.01 NHCL with 720 mg of citric
acid using Type II, USP apparatus (Paddle) rotating at a speed of
50 rpm. The results of the % drug released in tabulated below:
TABLE-US-00022 TABLE NO. 22 Results of the In vitro release of the
drug from three units of the dosage form in 500 ml of 0.01N HCl
with 720 mg citric acid EXAMPLE 12 EXAMPLE 13 Time in (N = 3) (N =
3) minutes % Dissolved % Dissolved 5 30 19 10 43 29 20 59 36 30 77
48 45 89 56 60 97 63
Example 14
TABLE-US-00023 [0197] TABLE 23 Immediate release solid dosage form
of Example 14 Description of mg per % by dosage form Ingredients
tablet weight Intragranular model drug 11.6 1.1 phase (Tapentadol
HCl) Methyl methacrylate 80.0 7.5 butyl methacrylate-
dimethylaminoethyl methacrylate copolymer (Eudragit .RTM. E PO)
Polyvinyl alcohol* 16.0 1.5 Acetaminophen granules 420.0 39.25
Extragranular Sodium bicarbonate 180.0 26.16 Magnesium Oxide 25.0
4.67 Silicified Micro- 193.4 15.6 crystalline cellulose (Prosolv
SMCC 90) Talc 7.0 0.65 Magnesium Stearate 7.0 0.65 **Polyvinyl
alcohol: Opadry .RTM. II clear 88 F59007
[0198] The tablets of Example 14 were subjected to in vitro
dissolution in 500 ml of 0.01N HCl using Type II, USP apparatus
(Paddle) rotating at a speed of 50 rpm. The results of the % drug
released in tabulated below:
TABLE-US-00024 TABLE 24 Results of the In vitro release of the drug
from two and four units of the dosage form in 500 ml of 0.01N HCl
Time in minutes N = 2 N = 4 5 41 33 10 59 48 15 75 55 30 91 65 45
94 67 60 99 69
Example 15
[0199] Example 15 illustrates the analysis of the values of the
C.sub.max obtained during the pharmacokinetic study. The graph
shows the number of subjects falling in five % range of reduction
in the C.sub.max. The graphical representation is provided in FIG.
17.
[0200] The pharmacokinetic parameters of one of the representative
abuse deterrent immediate release solid dosage form were evaluated
when administered at prescribed dose and when administered at more
than prescribed dose such as, for example, three units.
[0201] In order to evaluate this, a randomized open label three
treatment, single dose, crossover relative bioavailability and dose
proportionality study was carried out under fasting conditions.
Eighteen healthy human volunteers were dosed for the study of which
fifteen completed the study. The three groups that received the
abuse deterrent immediate release solid dosage form, were as
follows:
[0202] Treatment group A: This group received abuse deterrent
immediate release solid dosage form prepared as described in the
example 6B.
[0203] Treatment group B: This group received three units (more
than the prescribed number of units) of the abuse deterrent
immediate release solid dosage form prepared as described in the
example 6B.
[0204] Treatment group C: This group received single (prescribed
number of unit) of the solid dosage form prepared in conventional
manner, i.e without any abuse deterrent properties.
[0205] Post dose blood samples were collected at 0.25, 0.50, 0.75,
1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00,
and 12.00 hours. The Plasma concentrations obtained at various time
points were plotted for all the three group of volunteers. The
plasma levels of the group A were compared with the plasma levels
of the group B, in a dose proportionate manner.
[0206] The percentage reduction in the C.sub.max achieved by group
B treatment as compared to the C.sub.max achieved by group A
treatment values multiplied by three i.e (3.times.A) expected
C.sub.max (the value of Cmax that would be theoretically achieved
if three tablets of test product were taken, as shown in the table
below:
TABLE-US-00025 TABLE 25 Depicts percentage reduction in the Cmax
achieved by group B treatment as compared to the Cmax achieved by
group A treatment values multiplied by three volunteer Expected
Achieved % reduction in no (3A) (B) C.sub.max*from the expected 1
3906.3 2395.4 38.68 2 4209 4103.4 2.509 3 930.9 1308.8 -40.595 4
1291.2 995.6 22.89 5 2134.5 2159.6 -1.18 6 2984.7 2670.7 10.52 7
10257 7903.3 22.947 8 3915.3 2543 35.050 9 4760.1 2136.1 55.125 10
5625.9 4323.1 23.157 11 10925.7 7183.8 34.25 12 7286.7 3126.3
57.095 13 494.4 360 27.184 14 10583.1 6182.9 41.58 15 10829.4
6550.7 39.51 Average 5342.28 3596.18 32.684 *% reduction of
C.sub.max from expected = (C.sub.max expected - C.sub.max achieved)
* 100/C.sub.max expected ie. [(3A - B)*100]/3A
[0207] The results of the experiment indicate that when one of the
embodiments of the invention was tested the actual C.sub.max
achieved after administration of three tablets of the present
invention was lower as compared to the expected C.sub.max. This
shows that the immediate release biphasic matrix solid dosage form
of the present invention provides deterrence to abuse via
administration of more than the prescribed number of units. The
reduced C.sub.max would provide deterrence to the abuser who
attempts to abuse the active ingredient and achieve `high` by
taking more than prescribed number of units of the solid dosage
form concurrently.
Example 16
[0208] The intragranular phase was prepared by mixing drug and the
reverse enteric polymer and subjecting the mixture to hot melt
extrusion. The extrudates were milled and were subjected to X-ray
diffraction along with physical mixture of the drug and the reverse
enteric polymer, drug alone and the blend of Methyl methacrylate
and Diethyl aminoethyl methacrylate copolymer in the powder form
and polyvinyl alcohol but without drug (referred to as
placebo).
[0209] Table No. 26: Composition Details of the Intragranular
Phase
[0210] Procedure: The specified amounts of tapentadol, Methyl
methacrylate and Diethyl aminoethyl methacrylate copolymer in the
powder form and polyvinyl alcohol were mixed. The blend was
subjected to hot melt extrusion at a temperature of about
155.degree.-1600 C. The extrudates so prepared were milled and
sifted through suitable sieve. The milled extrudes were subjected
to XRD diffraction. Figure demonstrates that a solid dispersion of
tapendadol is obtained.
* * * * *
References