U.S. patent application number 13/946871 was filed with the patent office on 2014-02-27 for opioids for the treatment of the chronic obstructive pulmonary disease (copd).
This patent application is currently assigned to Euro-Celtique S.A.. The applicant listed for this patent is Euro-Celtique S.A.. Invention is credited to Wolfgang FLEISCHER, Petra LEYENDECKER, Karen REIMER.
Application Number | 20140057933 13/946871 |
Document ID | / |
Family ID | 34925285 |
Filed Date | 2014-02-27 |
United States Patent
Application |
20140057933 |
Kind Code |
A1 |
FLEISCHER; Wolfgang ; et
al. |
February 27, 2014 |
OPIOIDS FOR THE TREATMENT OF THE CHRONIC OBSTRUCTIVE PULMONARY
DISEASE (COPD)
Abstract
The present invention relates to an opioid controlled release
oral dosage form comprising at least one opioid for the manufacture
of a medicament to treat patients with Chronic Obstructive
Pulmonary Disease (COPD).
Inventors: |
FLEISCHER; Wolfgang;
(Ingelheim, DE) ; REIMER; Karen; (Hambach, DE)
; LEYENDECKER; Petra; (Wetzlar, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Euro-Celtique S.A. |
Luxembourg |
|
LU |
|
|
Assignee: |
Euro-Celtique S.A.
Luxembourg
LU
|
Family ID: |
34925285 |
Appl. No.: |
13/946871 |
Filed: |
July 19, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11570197 |
Mar 5, 2007 |
8518925 |
|
|
PCT/EP05/06155 |
Jun 8, 2005 |
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13946871 |
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Current U.S.
Class: |
514/282 |
Current CPC
Class: |
A61K 31/485 20130101;
A61P 11/00 20180101; A61K 2300/00 20130101; A61K 31/485 20130101;
A61P 43/00 20180101 |
Class at
Publication: |
514/282 |
International
Class: |
A61K 31/485 20060101
A61K031/485 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 8, 2004 |
EP |
04013468.6 |
Claims
1-13. (canceled)
14. A method of treating Chronic Obstructive Pulmonary Disease
(COPD) comprising administering to a patient in need thereof a
controlled release oral dosage form comprising an opioid
agonist.
15. The method of claim 14, wherein the dosage form provides an
effective treatment when administered every 12 hours at steady
state.
16. The method of claim 14, wherein the dosage form provides an
effective treatment when administered every 24 hours at steady
state.
17. The method of claim 14, wherein the dosage form is administered
to the patient twice daily.
18. The method of claim 14, wherein the opioid agonist is selected
from oxycodone, hydromorphone, propoxyphene, nicomorphine,
dihydrocodeine, diamorphine, papaveretum, codeine, ethylmorphine,
phenylpiperidine, methadone, dextropropoxyphene, buprenorphine,
pentazocine, tilidine, tramadol, hydrocodone, meperidine,
oxymorphone, alphaprodine, anileridine, dextromoramide, metopone,
levorphanol, phenazocine, etoheptazine, propiram, profadol,
phenampromide, thiambutene, pholcodeine, codeine, dihydrocodeinone,
fentanyl,
3-transdimethylamino-4-phenyl-4-trans-carbethoxy-.LAMBDA.'-cyclohexene,
3-dimethylamino-O-(4-methoxyphenyl-carbamoyl)-propiophenone oxime,
(-)-.beta.-2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphane,
(-)-2'-hydroxy-2-(3-methyl-2-butenyl)-9-methyl-5-phenyl-6,7-benzomorphane-
, pirinitramide,
(-)-.alpha.-5,9-diethyl-2'-hydroxy-2-methyl-6,7-benzomorphane,
ethyl
1-(2-dimethylaminoethyl)-4,5,6,7-tetrahydro-3-methyl-4-oxo-6-phenyl-indol-
-2-carboxylate,
1-benzoylmethyl-2,3-dimethyl-3-(m-hydroxy-phenyl)-piperidine,
N-allyl-7.alpha.(1-R-hydroxy-1-methylbutyl)-6,14-endo-ethanotetrahydronor-
oripavine, (+2'-hydroxy-2-methyl-6,7-benzomorphane,
noracylmethadol, phenoperidine, .alpha.-dl-methadol,
.alpha.-l-methadol, .beta.-dl-acetylmethadol,
.alpha.-l-acetylmethadol, .beta.-l-acetylmethadol, and sufetanil,
and pharmaceutically acceptable salts thereof.
19. The method of claim 18, wherein the opioid agonist is selected
from oxycodone, hydromorphone, propoxyphene, nicomorphine,
dihydrocodeine, diamorphine, papaveretum, codeine, ethylmorphine,
phenylpiperidine, methadone, dextropropoxyphene, buprenorphine,
pentazocine, tilidine, tramadol, and hydrocodone, and
pharmaceutically acceptable salts thereof.
20. The method of claim 18, wherein the opioid agonist is selected
from oxycodone, hydrocodone, hydromorphone, methadone, oxymorphone,
fentanyl, and sufentanil, and pharmaceutically acceptable salts
thereof.
21. The method of claim 14, wherein the dosage form further
comprises an opioid antagonist.
22. The method of claim 21, wherein dosage form is configured to
release the opioid agonist and the opioid antagonist in an
independent and invariant manner.
23. The method of claim 21, wherein the opioid antagonist is
selected from naltrexone, naloxone, nalmefene, nalorphine,
nalbuphine, naloxoneazinen, methylnaltrexone, ketylcyclazocine,
norbinaltorphimine, naltrindol, 6-.beta.-naloxol, and
6-.beta.-naltrexol, and pharmaceutically acceptable salts
thereof.
24. The method of claim 23, wherein the opioid antagonist is
selected from naltrexone, nalmefene, and naloxone, and
pharmaceutically acceptable salts thereof.
25. The method of claim 24, wherein the opioid antagonist is
naloxone or a pharmaceutically acceptable salt thereof.
26. The method of claim 25, wherein the naloxone or the
pharmaceutically acceptable salt thereof is present in the dosage
form in an amount range of 1 to 50 mg.
27. The method of claim 25, wherein the opioid agonist is present
in the dosage form in an amount that is therapeutically equivalent
to an amount of oxycodone or a pharmaceutically acceptable salt
thereof, and the amount of oxycodone or the pharmaceutically
acceptable salt thereof is in excess relative to the amount of
naloxone or the pharmaceutically acceptable salt thereof.
28. The method of claim 25, wherein the opioid agonist is present
in the dosage form in an amount that is therapeutically equivalent
to an amount of oxycodone or a pharmaceutically acceptable salt
thereof, and the amount of oxycodone or the pharmaceutically
acceptable salt thereof is in a weight ratio to the naloxone or the
pharmaceutically acceptable salt thereof ranging from 25:1 to
1:1.
29. The method of claim 28, wherein the amount of oxycodone or the
pharmaceutically acceptable salt thereof is in a weight ratio to
the naloxone or the pharmaceutically acceptable salt thereof
ranging from 5:1 to 1:1.
30. The method of claim 29, wherein the amount of oxycodone or the
pharmaceutically acceptable salt thereof is in a weight ratio to
the naloxone or the pharmaceutically acceptable salt thereof of
5:1, 4:1, 3:1, 2:1, or 1:1.
31. The method of claim 30, wherein the amount of oxycodone or the
pharmaceutically acceptable salt thereof is in a weight ratio to
the naloxone or the pharmaceutically acceptable salt thereof of
2:1.
32. The method of claim 14, wherein the opioid agonist is present
in the dosage form in an amount range that is therapeutically
equivalent to 10 to 150 mg of oxycodone or a pharmaceutically
acceptable salt thereof.
33. The method of claim 32, wherein the opioid agonist is present
in the dosage form in an amount range that is therapeutically
equivalent to 10 to 80 mg of oxycodone or a pharmaceutically
acceptable salt thereof.
34. The method of claim 21, wherein the opioid agonist is present
in the dosage form in an amount range that is therapeutically
equivalent to 10 to 150 mg of oxycodone or a pharmaceutically
acceptable salt thereof.
35. The method of claim 34, wherein the opioid agonist is present
in the dosage form in an amount range that is therapeutically
equivalent to 10 to 80 mg of oxycodone or a pharmaceutically
acceptable salt thereof.
36. The method of claim 25, wherein the opioid agonist is present
in the dosage form in an amount range that is therapeutically
equivalent to 10 to 150 mg of oxycodone or a pharmaceutically
acceptable salt thereof.
37. The method of claim 36, wherein the opioid agonist is present
in the dosage form in an amount range that is therapeutically
equivalent to 10 to 80 mg of oxycodone or a pharmaceutically
acceptable salt thereof.
38. The method of claim 31, wherein the opioid agonist is present
in the dosage form in an amount range that is therapeutically
equivalent to 10 to 150 mg of oxycodone or a pharmaceutically
acceptable salt thereof.
39. The method of claim 38, wherein the opioid agonist is present
in the dosage form in an amount range that is therapeutically
equivalent to 10 to 80 mg of oxycodone or a pharmaceutically
acceptable salt thereof.
40. The method of claim 14, wherein the dosage form further
comprises a sustained release matrix.
41. The method of claim 40 wherein the sustained release matrix
comprises an alkyl cellulose or a hydroxyalkyl cellulose.
42. The method of claim 41, wherein the sustained release matrix
comprises an alkyl cellulose.
43. The method of claim 42, wherein the alkyl cellulose is ethyl
cellulose.
Description
[0001] The invention concerns the treatment of Chronic Obstructive
Pulmonary Disease (COPD). In particular, the invention concerns the
use of opioids for the manufacture of preparations for the
treatment of COPD. The inventive preparations can be used to treat
dyspnea associated with COPD and the "pink puffer" type of COPD
patient, one of the two stereotypes in severe COPD.
BACKGROUND OF THE INVENTION
[0002] Chronic Obstructive Pulmonary Disease, or COPD for short, is
a progressive disease of the lungs that affects millions of people
each year. It is caused by blockage of the airways in the lungs,
and it has no cure.
[0003] COPD relates to a number of chronic lung disorders that
obstruct the airways, such as emphysema and chronic bronchitis.
Emphysema occurs when some of the air sacs deep in the lungs have
been damaged. This results in a smaller number of larger air sacs
that have poor gas exchange capabilities.
[0004] Dyspnea, the most disabling symptom, usually begins after
age 50 and worsens progressively. Large day-to-day variation in the
degree of dyspnea may indicate bronchospasm. Dyspnea is more severe
and more common among men. Wheezing, when present, is usually first
noted when the patient is supine. Later, it may occur in any
position and is usually associated with bronchospasm.
[0005] If hypoxemia develops, subtle signs of mental dysfunction,
such as an inability to concentrate and reduced short-term memory,
may occur. Hypercapnia may develop later and slowly lead to brain
swelling and further dysfunction, resulting in confusion, lethargy,
and increasing somnolence.
[0006] Signs of severe obstruction include pursed-lip breathing,
which delays airway closure so that a large tidal volume can be
maintained and respiratory muscles can function more efficiently;
breathing in the sitting position with elbows resting on the thighs
or a table, which may fixate the upper thorax and increase the
curvature of the diaphragm, making breathing more efficient; and
use of extrathoracic muscles (e.g. the sternocleidomastoid).
[0007] Exacerbations of obstructive bronchitis in COPD patients
usually result from infection with viruses, Haemophilus influenzae,
or Streptococcus pneumoniae. Fever and leukocytosis may not appear.
Worsening airway obstruction often leads to increasing dyspnea.
Hypoxemia or hypercapnia accompanying a respiratory infection may
lead to confusion and restlessness, which may be misinterpreted as
an age-related change.
[0008] In severe COPD, two stereotypes--the pink puffer and the
blue bloater--help define the extremes of the disease. Most
patients have features of both stereotypes. The pink puffer is
typically an asthenic, barrel-chested emphysematous patient who
exhibits pursed-lip breathing and has no cyanosis or edema.
Usually, such a patient uses extrathoracic muscles to breathe,
produces minimal sputum, and experiences little fluctuation in the
day-to-day level of dyspnea. Diaphragmatic excursions are reduced,
and breath and heart sounds are distant. The barrel-shaped chest is
non-specific because elderly persons commonly have increased lung
compliance and larger resting lung volumes. The blue bloater is
typically overweight, cyanotic, and edematous and has a chronic
productive cough. Elderly blue bloaters are uncommon because blue
bloaters often have cor pulmonale, which rapidly leads to death if
not treated appropriately.
[0009] Treatment for chronic bronchitis and emphysema is
palliative, not curative. It is considered successful when it
produces a favourable balance between symptomatic relief and
drug-related adverse effects.
[0010] Theophylline, besides being a bronchodilator, may also be a
mild respiratory stimulant.
[0011] Inhaled .beta..sub.2-symphathomimetics also are often
effective. Corticosteroids are beneficial during acute
exacerbations of bronchospasm in elderly patients with severe COPD
and may reduce the length of stay in the intensive care unit and in
the hospital. Long-term systemic corticosteroid therapy (prednisone
10 to 20 mg/day or its equivalent) is also beneficial in selected
patients with end-stage COPD in whom all other forms of therapy are
ineffective.
[0012] Hypercapnia commonly accompanies severe airway obstruction.
A rapid rise in the partial pressure of CO.sub.2 (Pco.sub.2) with a
drop in pH suggests that the patient has fatigued respiratory
muscles and needs more intensive therapy, perhaps including
ventilatory support.
[0013] Dyspnea thought to result from respiratory muscle fatigue
caused by an inappropriate amount of work for a given level of
ventilation or hypoxemia. Therefore, attempts are made to
strengthen respiratory muscles, reduce the amount of respiratory
muscle work, reduce oxygen requirements, and ensure adequate oxygen
delivery. Pursed-lip breathing may reduce dyspnea by allowing for
more complete emptying of the lungs, which in turn allows the
diaphragm to achieve a more efficient length. There is some
evidence that blowing cool air with a fan on the cheeks of patients
with COPD reduces the sensation of dyspnea.
[0014] Especially patients with severe emphysema of the pink puffer
type are symptom-limited due to dyspnea even at low level of
activity. However, no adequate medication is presently available to
treat severe dyspnea. Opioids have been suggested to be effective
for the treatment of dyspnea. However, since COPD is diagnosed
mainly in elderly people special care needs to be taken with regard
to the correct dosing of the opioids in respect to
drug-accumulation e.g. due to renal disfunction and the convenience
of application. Also long term compliance is highly desirable.
OBJECTS AND SUMMARY OF THE INVENTION
[0015] It is an object of the invention to provide an opioid oral
dosage form with a prolonged duration of action, preferably at
least 12 hours, more preferred at least 24 hours for the treatment
of moderate to severe COPD symptoms, preferably severe COPD
symptoms.
[0016] It is a further object of the invention to provide opioid
preparations as outlined above, which cause less side effects such
as respiratory depression and obstipation and which are provided
with abuse-preventing characteristics.
[0017] The invention further comprises a method of treating
patients with COPD symptoms with one of the inventive preparations,
and the use of such preparations in manufacturing pharmaceutical
preparations for the treatment of patients suffering from COPD.
DETAILED DESCRIPTION OF THE INVENTION
[0018] In the context of the invention, the term "opioid
composition" or "opioid" or "active" is used interchangeable and is
considered to include opioid agonists and opioid antagonists and
mixed opioid antagonists/agonists as well as mixtures thereof. The
preparations according to the present invention comprise at least
one opioid.
[0019] In the context of the invention the term "slow release
formulations or dosage forms" or "controlled release formulations
or dosage forms" "retard formulations or dosage forms" or
"sustained release formulations or dosage forms" or "formulations
or dosage forms with prolonged duration of action" are used
interchangeable and are understood to be formulations or dosage
forms that exhibit a prolonged release profile for the active
incorporated and which provide a sufficient therapeutic effect for
at least 12 hours at steady state.
[0020] The invention is premised on the fact that opioid agonists
are useful for the treatment of COPD-symptoms such as dyspnea. In
particular, the use of opioid sustained release oral dosage forms
results in better patient compliance and renders the patient on
constant medication more independent from taking medication during
day and night time. The minimum of the therapeutically necessary
drug can be administered, thereby reducing side effects
accumulation and the risk of addiction. In particular, combinations
of opioid agonists and antagonist are advantageous with respect to
reduced side effects and additionally reduce the risk of abuse.
Active Ingredients
[0021] According to the invention, opioid agonists comprise all
compounds that belong to class NO2A of opioid analgesics according
to the ATC Classification of the WHO, and that display a
therapeutic effect upon application in accordance with the
invention. The preparations according to the present invention
comprise at least one opioid. Preferably, an opioid agonist is
selected from the group of morphine, oxycodone, hydromorphone,
propoxyphene, nicomorphine, dihydrocodeine, diamorphine,
papavereturn, codeine, ethylmorphine, phenylpiperidine and
derivates thereof, methadone, dextropropoxyphene, buprenorphine,
pentazocine, tilidine, tramadol and hydrocodone. Further examples
for useable analgesics according to the invention are meperidine,
oxymorphone, alphaprodine, anileridine, dextromoramide, metopone,
levorphanol, phenazocine, etoheptazine, propiram, profadol,
phenampromide, thiambuten, pholcodeine, codeine, dihydrocodeinon,
fentanyl,
3-trans-dimethylamino-4-phenyl-4-trans-carbethoxy-.LAMBDA.'-cyclohexen,
3-dimethylamino-0-(4-methoxyphenyl-carbamoyl)-propiophenone oxime,
(-).beta.-2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphane,
(-)2'-hydroxy-2-(3-methyl-2-butenyl)-9-methyl-5-phenyl-6,7-benzomorphane,
pirinitramide, (-).alpha.-5,9-diethyl-T
hydroxy-2-methyl-6,7-benzomorphane, ethyl
1-(2-dimethylaminoethyl)-4,5,6,7-tetrahydro-3-methyl-4-oxo-6-phenyl-indol-
-2-carboxylate,
1-benzoylmethyl-2,3-dimethyl-3-(m-hydroxy-phenyl)-piperidine,
N-allyl-7.alpha.
(1-R-hydroxy-1-methylbutyl)-6,14-endo-ethanotetrahydronororipavine,
(-)2'-hydroxy-2-methyl-6,7-benzomorphane, noracylmethadol,
phenoperidine, .alpha.-d1-methadol, .alpha.-1-methadol,
.beta.-d1-acetylmethadol, .alpha.-1-acetylmethadol and
.beta.-1-acetylmethadol. These lists are not to be understood as
exclusive.
[0022] Especially preferred analgesically effective opiod agonists
are oxycodone, hydrocodone, hydromorphone, morphine, methadone,
oxymorphone, fentanyl and sufentanyl. More preferred embodiments
contain oxycodone or morphine.
[0023] According to the invention, antagonists comprise such
compounds that counteract opioid agonists (as defined earlier).
Such compounds can also be found in the ATC Classification of the
WHO. According to the invention, compounds are preferred that upon
application in accordance with the invention decrease the side
effects, the habituation effects and the addictive potential caused
by the opioid agonists. Antagonists can comprise among others,
naltrexone, naloxone, nalmefene, nalorphine, nalbuphine,
naloxoneazinen, methylnaltrexone, ketylcyclazocine,
norbinaltorphimine, naltrindol, 6-.beta.-naloxol and
6-.beta.-naltrexol.
[0024] Especially preferred antagonists comprise naltrexone,
nalmefene and naloxone. More preferred embodiments comprise
naloxone.
[0025] Most preferred embodiments of the invention comprise the
combination of oxycodone and naloxone in a sustained release oral
dosage form. Preferably, oxycodone is present in excess to the unit
dosage amount of naloxone.
[0026] In the case of oxycodone and naloxone, preferred weight
ratios of agonist to antagonist lie within a weight ratio range of
25:1 at maximum, preferably of 20:1 at maximum, especially
preferred are the weight ratio ranges 15:1 and 10:1 and more
preferred 5:1, 4:1, 3:1, 2:1 and 1:1.
[0027] The absolute amounts of agonist and antagonist to be used
depend on the choice of the active compounds. Preferably the
agonist and antagonist are released from the pharmaceutical
preparation only in an independent and invariant manner.
[0028] If oxycodone and naloxone are used for a combination
preparation, preferably between 10 and 150 mg, especially
preferably between 10 and 80 mg of oxycodone (typical amounts for
use) and preferably between 1 and 50 mg naloxone per unit dosage
are used.
[0029] In other preferred embodiments of the invention, the
preparations may comprise between 5 and 50 mg of oxycodone, between
10 and 40 mg of oxycodone, between 10 and 30 mg of oxycodone or
approximately 20 mg of oxycodone. Preferred embodiments of the
invention may also comprise preparations with between 1 and 40 mg
naloxone, 1 and 30 mg naloxone, 1 and 20 mg naloxone or between 1
and 10 mg naloxone per unit dosage.
[0030] Preferably, the ratio of oxycodone and naloxone has to be
chosen in such a way that release profiles for both active
substances guarantee and that the agonist can display its
therapeutic effect while the amount of the antagonist is chosen in
such a way that habituation- or addiction-promoting effects and
side effects of the agonist are reduced or abolished, without
(substantially) affecting the therapeutic effect of the agonist.
According to the invention, development of habituation and
addiction as well as obstipation and breath depression are to be
considered as side effects of therapeutically effective opioid
agonists.
[0031] In the context of this invention, all kinds of
pharmaceutically acceptable salts and derivatives (including
prodrugs) of the active ingredient may be used instead or together
with the active unmodified ingredient, in amounts equivalent to the
amount of unmodified active ingredient as indicated herein.
[0032] Oxycodone and naloxone may be present as their
hydrochloride, sulphate, bisulfate, tatrate, nitrate, citrate,
bitartrate, phosphate, malate, maleate, hydrobromide, hydroiodide,
fumarate or succinate.
Dosage Forms
[0033] Preferably the opioid is provided in an oral dosage form.
The oral dosage form may be designed as a controlled release
preparation or it may be a combined immediate release and
controlled release oral dosage form. The dosage form may thus e.g.
comprise a controlled-release portion outwardly coated with an
immediate-release formulation. The active ingredient may be the
same, or may be different in these different portions.
[0034] In certain embodiments, the oral dosage forms of the present
invention comprise an opioid combined with excipients, i.e.,
pharmaceutically acceptable organic or inorganic carrier substances
suitable for oral administration which are known in the art.
Suitable pharmaceutically acceptable carriers include but are not
limited to water salt solutions, alcohols, gum arabic, vegetable
oils, benzyl alcohols, polyethylene glycols, gelate, carbohydrates
such as lactose, amylose or starch, magnesium stearate talc,
silicic acid, viscous paraffin, perfume oil, digestible long chain
substituted or unsubstituted hydrocarbons such as fatty acid
monoglycerides and diglycerides, pentaerythritol fatty acid esters,
hydrophilic or hydrophobic polymers, such as cellulose and
cellulose derivatives, such as alkylcellulose or
hydroxyalkylcellulose, acrylic resins, such as the polymers known
under the Eudragit.RTM. trade name, polyvinylpyrrolidone, etc. The
pharmaceutical compositions can be sterilized and if desired mixed
with auxiliary agents, e.g., lubricants, preservatives,
stabilizers, wetting agents, emulsifiers, salts for influencing
osmotic pressure buffers, coloring, flavoring and/or aromatic
substances.
[0035] The oral pharmaceutical compositions of the present
invention can be in the form of tablets, coated tablets, liquids,
drops, gelcaps, troches, lozenges, aqueous or oily suspensions,
multiparticulate formulations including dispersable powders,
granules, pellets, matrix spheroids, beads or coated inert beads,
emulsions, hard or soft capsules or syrups or elixirs,
microparticles (e.g., microcapsules, microspheres and the like),
buccal tablets, etc.
[0036] The oral compositions may be prepared according to methods
known in the art and such compositions may contain one or more
agents selected from the group consisting of inert, non-toxic
pharmaceutically acceptable excipients which are suitable for the
manufacture of tablets. Such excipients include, for example an
inert diluent such as lactose; granulating and disintegrating
agents such as cornstarch; binding agents such as starch; and
lubricating agents such as magnesium stearate. The tablets may be
uncoated or they may be coated by known techniques for elegance or
to delay release of the active ingredients. Formulations for oral
use may also be presented as hard gelatin capsules wherein the
active ingredients is mixed with an inert diluent.
[0037] Aqueous suspensions preferably contain the opioid in a
mixture that has one or more excipients suitable as suspending
agents, for example, pharmaceutically acceptable synthetic gums
such as hydroxypropylmethylcellulsoe or natural gums. Oily
suspensions may be formulated by suspending the above-identified
combination of drugs in a vegetable oil or mineral oil. The oily
suspensions may contain at thickening agent such as beeswax or
cetyl alcohol. A syrup, elixir, or the like can be used, wherein a
sweetened vehicle is employed.
[0038] The pharmaceutical oral compositions of the present
invention comprise an effective amount of opioid (at least one) in
a sustained release formulations. For example, a sustained release
carrier can be included in the formulation to provide a release of
the opioid antagonist over a 12 to 24 hour period. As used herein
an effective amount of opioid means that the amount is sufficient
to provide the desired therapeutic effect within the desired period
of time. The therapeutic effect may also be the effect of an
antagonist.
[0039] For example the sustained release oral dosage form which is
effective for 24 hours at steady state conditions includes from
about 1 to about 640 mg of oxycodone or a pharmaceutically
acceptable salt thereof (e.g., oxycodone hydrochloride). Preferably
the sustained release oral dosage form includes from about 5 to
about 500 mg oxycodone or a pharmaceutically acceptable salt
thereof, more preferably from about 10 to about 320 mg oxycodone or
a pharmaceutically acceptable salt thereof and even more preferably
from about 10 to about 160 mg oxycodone or a pharmaceutically
acceptable salt thereof.
[0040] For example the sustained release oral dosage form which is
effective for 12 hours at steady state conditions includes from
about 1 to about 160 mg of oxycodone or a pharmaceutically
acceptable salt thereof (e.g., oxycodone hydrochloride).
[0041] Other opioids may be present in amounts that are equivalent
to the above mentioned oxycodone amounts with regard to the desired
therapeutic effect.
[0042] In certain preferred embodiments, the oral dosage form
includes a sustained-release material which is incorporated into a
matrix along with the at least one opioid, to provide for the
sustained release of the agent. The sustained-release material may
be hydrophobic or hydrophilic as desired. The oral dosage form of
the present invention may be prepared as granules, spheroids,
matrix multiparticulates, etc. which comprise the at least one
opioid in a sustained release matrix which may be compressed into a
tablet or encapsulated. The oral dosage form of the present
invention may optionally include other pharmaceutically acceptable
ingredients (e.g. diluents, binders, colorants, lubricants,
etc.).
[0043] In certain other embodiments, the oral dosage form of the
present invention may be an osmotic dosage form having a push or
displacement composition as one of the layers of a bilayer core for
pushing the at least one opioid from the dosage form, and a
semipermeable wall composition surrounding the core, wherein the
wall has at least one exit means or passageway for delivering the
at least opioid from the dosage form. Alternatively, the core of
the osmotic dosage form may comprise a single layer core including
a controlled release polymer and the at least one opioid.
[0044] Preferably the dosage forms of the present invention
provides an effect for at least about 12 hours after
administration.
Sustained-Release Matrix Formulations
[0045] In preferred embodiments of the present invention, the
formulation can be a matrix with the opioid interdispersed in the
sustained release carrier, to provide for the sustained release of
the opioid.
[0046] A non-limiting list of suitable sustained-release materials
which may be included in a sustained-release matrix according to
the invention include hydrophilic and/or hydrophobic materials,
such as gums, cellulose ethers, acrylic resins, protein derived
materials, waxes, shellac, and oils such as hydrogenated castor oil
and hydrogenated vegetable oil. However, any pharmaceutically
acceptable hydrophobic or hydrophilic sustained-release material
which is capable of imparting sustained-release of the opioid may
be used in accordance with the present invention. Preferred
sustained-release polymers include alkylcelluloses such as
ethylcellulose, acrylic and methacrylic acid polymers and
copolymers; and cellulose ethers, especially hydroyalkylcelluloses
(especially hydroxypropylmethylcellulose) and
carboxyalkylcelluloses. Preferred acrylic and methacrylic acid
polymers and copolymers include methyl methacrylate, methyl
methacylate copolymers, ethoxyethyl methacrylates, ethyl acrylate,
trimethyl ammonioethyl methacrylate, cyanoethyl methacrylate,
aminoalkyl methacrylate copolymer, poly(acrylic acid),
Poly(methacylic acid), methacrylic acid alkylamine copolymer,
poly(methyl)methacrylate, poly(methacrylic acid) (anhydride),
polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride),
and glycidyl methacrylate copolymers. Certain preferred embodiments
utilise mixtures of any of the foregoing sustained-release
materials in the matrix of the invention.
[0047] The matrix also may include a binder. In such embodiments,
the binder preferably contributes to the sustained-release of the
opioid from the sustained-release matrix.
[0048] If an additional hydrophobic binder material is included, it
is preferably selected from natural and synthetic waxes, fatty
acids, fatty alcohols, and mixtures of the same. Examples include
beeswax, carnauba wax. stearic acid and stearyl alcohol. This list
is not meant to be exclusive. In certain preferred embodiments, a
combination of two or more hydrophobic binder materials are
included in the matrix formulations.
[0049] Preferred hydrophobic binder materials which may be used in
accordance with the present invention include digestible, long
chain (C.sub.8-C.sub.50, especially C.sub.12-C.sub.40), substituted
or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols,
glyceryl esters of fatty acids, mineral and vegetable oils, natural
and synthetic waxes and polyakylene glycols. Hydrocarbons having a
melting point of between 25.degree. and 90.degree. C. are
preferred. Of the long-chain hydrocarbon binder materials, fatty
(aliphatic) alcohols are preferred in certain embodiments. the oral
dosage form may contain up to 80% (by weight) of at least one
digestible, long chain hydrocarbon.
[0050] In certain embodiments, the hydrophobic binder material may
comprise natural or synthetic waxes, fatty alcohols (such as
lauryl, myristyl, stearyl, cetyl or preferably cetostearyl
alcohol), fatty acids, including but not limited to fatty acid
esters, fatty acid glycerides (mono-, di-, and tri-glycerides),
hydrogenated fats, hydrocarbons, normal waxes, stearic acid,
stearyl alcohol and hydrophobic and hydrophilic materials having
hydrocarbon backbones. Suitable waxes include, for example,
beeswax, glycowax, castor wax and carnauba wax. For purposes of the
present invention, a wax-like substance is defined as any material
which is normally solid at room temperature and has a melting point
of from about 30 to about 100.degree. C.
[0051] In certain preferred embodiments, the dosage form comprises
a sustained release matrix comprising the opioid and at least one
water soluble hydroxyalkyl cellulose, at least one
C.sub.12-C.sub.36, especially C.sub.14-C.sub.22, aliphatic alcohol
and, optionally, at least one polyalkylene glycol. The hydroxyalkyl
cellulose is preferably a hydroxy C.sub.1-C.sub.6 alkyl cellulose,
such as hydroxypropylcellulose, hydroxypropylmethylcellulose and,
especially, hydroxethyl cellulose. The amount of the at least one
hydroxyalkyl cellulose in the present oral dosage form may be
determined, inter alia, by the precise rate of opioid release
required.
[0052] In certain other preferred embodiments, the dosage form
comprises a sustained release matrix comprising the at least one
opioid and at least one acrylic resin, at least one
C.sub.12-C.sub.36, especially C.sub.14-C.sub.22, aliphatic alcohol
and, optionally, at least one polyalkylene glycol. The acrylic
resin includes but is not limited to acrylic acid and methyacrylic
acid copolymers, methyl methacrylate copolymers, ethoxyethyl
methacrylates, cynaoethyl methacrylate, poly(acrylic acid),
poly(methacrylic acid), methacrylic acid alkylamide copolymer,
poly(methyl methacrylate), polymethacrylate, poly(methyl
methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate
copolymer, poly(methacrylic acid anhydride) and glycidyl
methacrylate copolymers. In certain preferred embodiments, the
acrylic polymer is comprised of one or more ammonio methacrylate
copolymers. Ammonio methacrylate copolymers are well known in the
art, and are described as fully polymerised copolymers of acrylic
and methacrylic acid esters with a low content of quaternary
ammonium groups. Preferably the acrylic resin is an acrylic polymer
or an acrylic copolymer such as poly(meth)acrylate or methacrylic
acid-ethyl acrylate copolymer or poly(meth)acrylate copolymerised
with trimethyl ammonium(meth)acrylate chloride, such as
poly(meth)acrylate with 5% trimethyl ammonium methacrylate
chloride. The amount of the at least one acrylic resin in the
present oral dosage form may be determined, inter alia, by the
precise rate of opioid release required. In order to obtain a
desirable dissolution profile, it may be necessary to incorporate
two or more ammonio methacrylate copolymers having differing
physical properties, such as different molar ratios of the
quaternary ammonium groups to the neutral (meth)acrylic esters.
Certain methacrylic acid ester-type polymers are useful for
preparing pH-dependent matrices which may be used in accordance
with the present invention. For example, there are a family of
copolymers synthesized from diethylaminoethyl methacrylic acid
copolymer or polymeric methacrylates, commercially available as
Eudragit.RTM. from Rohm Tech, Inc. There are several different
types of Eudragit.RTM.. For example, Eudragit E is an example of a
methacrylic acid copolymer which does not swell at about pH<5.7
and is soluble at about pH>6. Eudragit S does not swell at about
pH<6.5 and is soluble at about pH>7. Eudragit RL and Eudragit
RS are water swellable, and the amount of water absorbed by these
polymers is pH-dependent, however, dosage forms with Eudragit RL
and RS are pH-independent. In certain preferred embodiments, the
acrylic matrix comprises a mixture of two acrylic resins
commercially available from Rohm Pharma under the Tradenames
Eudragit.RTM. RL30D and Eudragit.RTM. RS30D, respectively.
Eudragit.RTM. RL30D and Eudragit.RTM. RS30D are copolymers of
acrylic and methacrylic esters with a low content of quaternary
ammonium groups, the molar ratio of ammonium groups to the
remaining neutral (meth)acrylic esters being 1:20 in Eudragit.RTM.
RL30D and 1:40 in Eudragit.RTM. RS30D. The mean molecular weight is
about 150,000. The code designations RL (high permeability) and RS
(low permeability) refer to the permeability properties of these
agents. Eudragit.RTM. RL/RS mixtures are insoluble in water and in
digestive fluids. However, coatings formed from the same are
swellable and permeable in aqueous solutions and digestive fluids.
The Eudragit.RTM. RL/RS dispersions of the present invention may be
mixed together in any desired ration in order to ultimately obtain
a controlled-release formulation having a desirable dissolution
profile. Desirable controlled-release formulations may be obtained,
for instance, from a retard matrices derived from Eudragit.RTM. RL,
Eudragit.RTM. RL and Eudragit.RTM. RS, and Eudragit.RTM. RL and
Eudragit.RTM. RS. Of course, one skilled in the art will recognize
that other acrylic polymers may also be used, such as, for example,
Eudragit.RTM. L.
[0053] The aliphatic alcohol may be, for example, lauryl alcohol,
myristyl alcohol, cetostearyl alcohol or stearyl alcohol. In
particularly preferred embodiments of the present oral dosage form,
however, the at least one aliphatic alcohol is cetyl alcohol or
cetostearyl alcohol. the amount of the aliphatic alcohol in the
present oral dosage form may be determined, as above, by the
precise rate of opioid release required. It may also depend on
whether at least one polyalkylene glycol is present in or absent
form the oral dosage form. In the absence of at least one
polyalylene glycol, the oral dosage form preferably contains
between about 20% and about 50% (by wt) of the aliphatic alcohol.
When a polyalkylene glycol is present in the oral dosage form, then
the combined weight of the aliphatic alcohol and the polyalkylene
glycol preferably constitutes between about 20% and about 50% (by
wt) of the total dosage form.
[0054] In one preferred embodiment, the ration of, e.g., the at
least one hydroxyalkyl cellulose or acrylic resin to the at least
one aliphatic alcohol/polyalkylene glycol determines, to a
considerable extent, the release rate of the opioid from the
formulation. In certain embodiments, a ration of the hydroxyalkyl
cellulose to the aliphatic alcohol/polyalkylene glycol of between
1:1 and 1:4 is preferred, with a ratio of between 1:2 and 1:3 being
particularly preferred.
[0055] In certain embodiments, the polyalkylene glycol may be, for
example, polypropylene glycol, or polyethylene glycol which is
preferred. The average molecular weight of the at least one
polyallylene glycol is preferably between 1,000 and 15,000,
especially between 1,500 and 12,000.
[0056] Another suitable sustained-release matrix comprises an
alkylcellulose (especially ethylcellulose), a C.sub.12 to C.sub.36
aliphatic alcohol and, optionally, a polyalkylene glycol.
[0057] In addition to the above ingredients, a sustained-release
matrix may also contain suitable quantities of other materials,
e.g., diluents, lubricants, binders, granulating aids, colorants,
flavorants and glidants that are conventional in the pharmaceutical
art.
[0058] In order to facilitate the preparation of a solid,
sustained-release oral dosage form according to this invention
incorporation the opioid in the matrix may be effected, for
example, by: [0059] (a) forming granules comprising at least one
hydrophobic and/or hydrophilic material as set forth above (e.g., a
water soluble hydroxyalkyl cellulose) together with the opioid;
[0060] (b) mixing the granules containing at lest one hydrophobic
and/or hydrophilic material with at least one C.sub.12-C.sub.36
aliphatic alcohol, (and, in case, other matrix components) and
[0061] (c) optionally, compressing and shaping the granules.
[0062] The granules may be formed by any of the procedures
well-known to those skilled in the art of pharmaceutical
formulation. For example, in one preferred method, the granules may
be formed by wet granulating hydroxyalkyl cellulose/opioid with
water. In a particularly preferred embodiment of this process, the
amount of water added during the wet granulation step is preferably
between 1.5 and 5 times, especially between 1.75 and 3.5 times, the
dry weight of opioid.
[0063] A sustained-release matrix can also be prepared by, e.g.,
melt-granulation or melt-extrusion techniques. Generally,
melt-granulation techniques involve melting a normally solid
hydrophobic binder material, e.g., a wax, and incorporating a
powdered drug therein. To obtain a sustained release dosage form,
it may be necessary to incorporate a hydrophobic sustained-release
material, e.g. ethylcellulose or a water-insoluble acrylic polymer,
into the molten wax hydrophobic binder material. Examples of
sustained-release formulations prepared via melt-granulation
techniques are found, e.g., in U.S. Pat. No. 4,861,598
(incorporated by reference).
[0064] The additional hydrophobic binder material may comprise one
or more water-insoluble wax-like thermoplastic substances possibly
mixed with one or more wax-like thermoplastic substances being less
hydrophobic than said one or more water-insoluble wax-like
substances in the formulation should be substantially
non-degradable and insoluble in gastrointestinal fluids during the
initial release phases. Useful water-insoluble wax-like binder
substances may be those with a water-solubility that is lower than
about 1:5,000 (w/w).
[0065] Extruded formulations employing starch, as e.g. disclosed in
DE 19918325 A1 (incorporated by reference), can be advantageously
employed in the context of the invention.
[0066] The preparation of a suitable melt-extruded matrix according
to the present invention may, for example, include the steps of
blending the opioid, together with a sustained release material and
preferably a binder material to obtain a homogenous mixture. The
homogenous mixture is then heated to a temperature sufficient to at
least soften the mixture sufficiently to extrude the same. The
resulting homogenous mixture is then extruded, e.g., using a
twin-screw extruder, to form strands. The extrudate is preferably
cooled and cut into multiparticulates by any means known in the
art. The matrix multiparticulates are then divided into unit doses.
The extrudate preferably has a diameter of from about 0.1 to about
5 mm and provides sustained release of the opioid for a time period
of at least about 24 hours.
[0067] An optional process for preparing the melt extruded
formulations of the present invention includes directly metering
into an extruder a hydrophobic sustained release material, the at
least one opioid and an optional binder material; heating the
homogenous mixture; extruding the homogenous mixture to thereby
form stands; cooling the strands containing the homogeneous
mixture; cutting the strands into matrix multiparticulates having a
size from about 0.1 mm to about 12 mm; and dividing said particles
into unit doses. In this aspect of the invention a relatively
continuous manufacturing procedure is realized.
[0068] Plasticizers, such as those described above, may be included
in melt-extruded matrices. The plasticizer is preferably included
as from about 0.1 to aobut 30% by weight of the matrix. Other
pharmaceutical excipients, e.g., talc, mono or poly saccharides,
colorants, flavorants, lubricants and the like may be included in
the sustained release matrices of the present invention as desired.
The amounts included will depend upon the desired characteristic to
be achieved.
[0069] The diameter of the extruder aperture or exit port can be
adjusted to vary the thickness of the extruded strands.
Furthermore, the exit part of the extruder need not be round; it
can be oblong, rectangular, etc. The exiting strands can be reduced
to particles using a hot wire cutter, guillotine, etc.
[0070] A melt extruded matrix multiparticulate system can be, for
example, in the form of granules, spheroids or pellets depending
upon the extruder exit orifice. For purposes of the present
invention, the terms "melt-extruded matrix multiparticulate(s)" and
"melt-extruded matrix multiparticulate system(s)" and
"melt-extruded matrix particles" shall refer to a plurality of
units, preferably within a range of similar size and/or shape and
containing one or more actives and one or more excipients,
preferably including a hydrophobic sustained release material as
described herein. Preferably the melt-extruded matrix
multiparticulates will be of a range of from about 0.1 to about 12
mm in length and have a diameter of from about 0.1 to about 5 mm.
In addition, it is to be understood that the melt-extruded matrix
multiparticulates can be any geometrical shape within this size
range. In certain embodiments, the extrudate may simply be cut into
desired lengths and divided into unit doses of the therapeutically
active agent without the need of a spheronization step.
[0071] In one preferred embodiment, oral dosage forms are prepared
that include an effective amount of melt-extruded matrix
multiparticulates within a capsule. for example, a plurality of the
melt-extruded matrix multiparticulates may be place in a gelatin
capsule in an amount sufficient to provide an effective sustained
release dose when ingested and contacted by gastrointestinal
fluid.
[0072] In another embodiment, a suitable amount of the
multiparticulate extrudate is compressed into an oral tablet using
conventional tableting equipment using standard techniques.
Techniques and compositions for making tablets (compressed and
molded), capsules (hard and soft gelatin) and pills are also
described in Remington's Pharmaceutical Sciences, (Arthur Oso,
editor), 1553-1593 (1980)
[0073] In yet another preferred embodiment, the extrudate can be
shaped into tablets as set forth in U.S. Pat. No. 4,957,681
(Klimesch, et. al.).
[0074] Optionally, the sustained-release matrix multiparticulate
systems, tablets, or capsules can be coated with a sustained
release coating such as the sustained release coatings described
herein. Such coatings preferably include a sufficient amount of
hydrophobic and/or hydrophilic sustained-release material to obtain
a weight gain level from about 2 to about 25 percent, although the
overcoat may be greater depending upon, e.g., the desired release
rate.
[0075] The dosage forms of the present invention may further
include combinations of melt-extruded matrix multiparticulates
containing the at least one opioid. Furthermore, the dosage forms
can also include an amount of an immediate release therapeutically
active opioid for prompt therapeutic effect. The immediate release
opioid may be incorporated, e.g., as separate multiparticulates
within a gelatin capsule, or may be coated on the surface of, e.g.,
melt-extruded matrix multiparticulates.
[0076] The sustained-release profile of the melt-extruded
formulations of the invention can be altered, for example, by
varying the amount of sustained-release material, by varying the
amount of plasticizer relative to other matrix constituents, by
varying the amount of hydrophobic material, by the inclusion of
additional ingredients or excipients, by altering the method of
manufacture, etc.
[0077] In other embodiments of the invention, melt-extruded
formulations are prepared without the inclusion of the opioid,
which is added thereafter to the extrudate. Such formulations
typically will have the opioid blended together with the extruded
matrix material, and then the mixture would be tableted in order to
provide a slow release formulation. Such formulations may be
advantageous, for example, when the therapeutically active agent
included in the formulations is sensitive to temperatures needed
for softening the hydrophobic material and/or the retardant
material.
[0078] Typical melt-extrusion production systems suitable for use
in accordance with the present invention include a suitable
extruder drive motor having variable speed and constant torque
control, start-stop controls, and a meter. In addition, the
production system will include a temperature control console which
includes temperature sensors, cooling means and temperature
indicators throughout the length of the extruder. In addition, the
production system will include an extruder such as a twin-screw
extruder which consists of two counter-rotating intermeshing screws
enclosed within a cylinder of barrel having an aperture or die at
the exit thereof. The feed materials enter through a feed hopper
and are moved through the barrel by the screws and are forced
through the die into strands which are thereafter conveyed such as
by a continuous movable belt to allow for cooling and being
directed to a pelletizier or other suitable device to render the
extruded ropes into the matrix multiparticulate system. The
pelletizer can consist of rollers, fixed knife, rotating cutter and
the like. Suitable instruments and systems are available from
distributors such as C.W. Brabender Instruments, Inc. of South
Hackensack, N.J. Other suitable apparatus will be apparent to those
of ordinary skill in the art.
[0079] In the preparation of melt-extruded matrix multiparticulates
as set forth above the amount of air included in the extrudate can
be controlled and the release rate of the at least one opioid
thereof may be altered.
[0080] Thus the melt-extruded is prepared in a manner which
substantially excludes air during the extrusion phase of the
process. This may be accomplished, for example, by using a
Leistritz extruder having a vacuum attachment. The extruded matrix
multiparticulates prepared according to the invention using a
Leistritz extruder under vacuum provides a melt-extruded product
having different physical characteristics. In particular, the
extrudate is substantially non-porous when magnified, e.g., using a
scanning electron microscope. Such substantially non-porous
formulations may provide a faster release of the therapeutically
active agent, relative to the same formulation prepared without
vacuum. Scanning electron micrographs of the matrix
multiparticulates prepared using an extruder under vacuum appear
very smooth, as compared to multiparticulates prepared without
vacuum. It has been observed that in at least certain formulations,
the use of extrusion under vacuum provides an extruded matrix
multiparticulates product which is more pH-dependent than its
counterpart formulation prepared without vacuum.
[0081] Alternatively, the melt-extruded product is prepared using a
Werner-Pfleiderer twin screw extruder.
[0082] In certain embodiments, a spheronizing agent is added to a
granulate or matrix multiparticulate and then spheronized to
produce sustained release spheroids. The spheroids are then
optionally overcoated with a sustained release coating by methods
such as those described above.
[0083] Spheronizing agents which may be used to prepare the matrix
multiparticulate formulations of the present invention include any
art-known spheronizing agent.
[0084] Cellulose derivatives are preferred, and microcrystalline
cellulose is especially preferred. A suitable microcrystalline
cellulose is, for example, the material sold as Avicel PH 101
(TradeMark, FMC Corporation). The spheronizing agent is preferably
included as about 1 to about 99% of the matrix multiparticulate by
weight.
[0085] In certain embodiments, in addition to the active ingredient
and spheronizing agent, the spheroids may also contain a binder.
Suitable binders, such as low viscosity, water soluble polymers,
will be well known to those skilled in the pharmaceutical art.
However, water soluble hydroxy lower alkyl cellulose, such as
hydroxy propyl cellulose, are preferred. Additionally (or
alternatively) the spheroids may contain a water insoluble polymer,
especially an acrylic polymer, an acrylic copolymer, such as a
methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.
[0086] In certain embodiments, a sustained release coating is
applied to the sustained release spheroids, granules, or matrix
multiparticulates. In such embodiments, the sustained-release
coating may include a water insoluble material such as (a) a wax,
either alone or in admixture with a fatty alcohol; or (b) shellac
or zein. The coating is preferably derived from an aqueous
dispersion of the hydrophobic sustained release material.
[0087] In certain embodiments, it is necessary to overcoat the
sustained release spheroids, granules, or matrix multiparticulates
comprising the opioid and sustained release carrier with a
sufficient amount of the aqueous dispersion of, e.g.,
alkylcellulose or acrylic polymer, to obtain a weight gain level
form about 2 to about 50%, e.g., about 2 to about 25%, in order to
obtain a sustained-release formulation. The overcoat may be lesser
or greater depending upon, e.g., the desired release rate, the
inclusion of plasticizer in the aqueous dispersion and the manner
of incorporation of the same. Cellulosic materials and polymers,
including alkylcelluloses, are sustained release materials well
suited for coating the sustained release spheroids, granules, or
matrix multiparticulates according to the invention. Simply by way
of example, one preferred alkylcellulosic polymer is
ethylcellulose, although the artisan will appreciate that other
cellulose and/or alkylcellulose polymers may be readily employed,
singly or in any combination, as all or part of a hydrophobic
coating according to the invention.
[0088] One commercially-available aqueous dispersion of
ethylcellulose is Aquacoat.RTM. (FMC Corp., Philadelphia, Pa.,
U.S.A.). Aquacoat.RTM. is prepared by dissolving the ethylcellulose
in a water-immiscible organic solvent and then emulsifying the same
in water in the presence of a surfactant and a stabilizer. After
homogenization to generate submicron droplets, the organic solvent
is evaporated under vacuum to form a pseudolatex. The plasticizer
is not incorporated in the pseudolatex during the manufacturing
phase. Thus, prior to using the same as a coating, it is necessary
to intimately mix the Aquacoat.RTM. with a suitable plasticizer
prior to use.
[0089] Another aqueous dispersion of ethylcellulose is commercially
available as Surelease.RTM. (Colorcon, Inc., Weset Point, Pa.,
U.S.A.). This product is prepared by incorporating plasticizer into
the dispersion during the manufacturing process. A hot melt of a
polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic
acid) is prepared as a homogeneous mixture, which is then diluted
with an alkaline solution to obtain an aqueous dispersion which can
be applied directly to the sustained release spheroids, granules,
or matrix multiparticulates.
[0090] In other preferred embodiments of the present invention, the
sustained release material comprising the sustained-release coating
is a pharmaceutically acceptable acrylic polymer, including but not
limited to acrylic acid and methacrylic acid copolymers, methyl
methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl
methacrylate, poly(acrylic acid), poly(methacrylic acid),
methacrylic acid alkylamide copolymer, poly(methyl methacrylate)),
polymethacrylate, poly(methyl methacrylate) copolymer,
polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic
acid anhydride), and glycidyl methacrylate copolymers. Useful
acrylic polymers are the resins known under the Tradename
Eudragit.RTM., commercially available from Rohm Pharma. These
acrylic resins can be tailored to provide a pH dependent or a pH
independent release rate of the active.
[0091] In addition to the above ingredients, the spheroids,
granules or matrix multiparticulates may also contain suitable
quantities of other materials, e.g., diluents, lubricants, binders,
granulating aids, colorants, flavorants and glidants that are
conventional in the pharmaceutical art in amounts up to about 50%
by weight of the formulation if desired. The quantities of these
additional materials will be sufficient to provide the desired
effect to the desired formulation.
[0092] Specific examples of orally acceptable carriers and
excipients that may be used to formulate oral dosage forms are
described in the Handbook of Pharmaceutical Excipients, American
Pharmaceutical Association (1986).
[0093] It has further been found that the addition of a small
amount of talc to the sustained release coating reduces the
tendency of the aqueous dispersion to stick during processing, and
acts as a polishing agent.
[0094] If oxycodone is used for the preparation the formulation is
chosen the matrix comprises at least one acrylic resin and at least
one C.sub.12-C.sub.36 aliphatic alcohol as they are described
above. The preparation is preferably accomplished by the above
described granulation method with the above described preferred
amounts of ingredients.
[0095] If oxycodone and naloxone are used for a combination
preparation the formulation is chosen to ensure that the active
compounds are released from the preparation in a sustained,
independent and invariant manner. Preferably those formulations are
storage stable.
[0096] The terms "released from the preparation in a sustained,
independent and invariant manner" and "storage stable" as used
herein are defined as in PCT/EP 03/03541.
[0097] If oxycodone and naloxone are used for a combination
preparation the formulation is chosen that it comprises a release
matrix that has the character of a substantially non-water- or
non-buffer-swellable and non-erosive diffusion matrix as defined in
PCT/EP 03/0354. PCT/EP 03/0354 is incorporated by reference.
[0098] If oxycodone and naloxone are used for a combination
preparation a formulation is especially preferred that comprises
ethylcellulose or Surelease.RTM. E-7-7050 as a matrix-building
substance, stearyl alcohol as fatty alcohol, magnesium stearate as
lubricant, lactose as filler and povidone as a granulating aid.
[0099] Such preparations can be produced as all common application
forms which, on principle, are suitable for retardation
formulations and which ensure that the active compounds are
released in a manner as outlined above. Especially suitable are
tablets, multi-layer tablets and capsules. Additional application
forms like granules or powders can be used, with only those
applications forms being admissible that provide a sufficient
retardation and a release behaviour as outlined above.
[0100] Such pharmaceutical preparations may also comprise film
coatings. However, it has to be ensured that the film coatings do
not negatively influence the release properties of the active
compounds from the matrix and the storage stability of the active
compounds within the matrix. Such film coatings may be colored or
may comprise a initial dosage of the active compounds if required.
The active compounds of this initial dosage will be immediately
released so that the therapeutically effective blood plasma level
is reached very quickly.
[0101] A detailed description of the preparation of these
oxycodone/naloxone combination preparations can be taken from
PCT/EP 03/03541.
Process for Preparing Matrix Beads
[0102] Controlled-release dosage forms according to the present
invention may also be prepared as matrix beads formulations. The
matrix beads include a spheronising agent and the at least one
opioid.
[0103] The at least one opioid preferably comprises from about 0.01
to about 99% by weight of the matrix bead by weight. It is
preferable that the at least one opioid is included as about 0.1 to
about 50% by weight of the matrix bead.
[0104] Spheronising agents which may be used to prepare the matrix
bead formulations of the present invention include any art-known
spheronising agent. Cellulose derivatives are preferred, and
microcrystalline cellulose is especially preferred. A suitable
microcrystalline cellulose is, for example, the material sold as
Avicel PH 101 (TradeMark, FMC Corporation). The spheronising agent
is preferably included as about 1 to about 99% of the matrix bead
by weight.
[0105] In addition to the active ingredient and spheronizing agent,
the spheroids may also contain a binder. Suitable binders, such as
low viscosity, water soluble polymers, will be well known to those
skilled in the pharmaceutical art. However, water soluble hydroxy
lower alkylcellulose, such as hydroxypropylcellulose, are
preferred.
[0106] In addition to the at least one opioid and spheronizing
agent, the matrix bead formulations of the present invention may
include a controlled release material such as those described
hereinabove. Preferred controlled-release materials for inclusion
in the matrix bead formulations include acrylic and methacrylic
acid polymers or copolymers, and ethylcellulose. When present in
the formulation, the controlled-release material will be included
in amounts of from about 1 to about 80% of the matrix bead, by
weight. The controlled-release material is preferably included in
the matrix bead formulation in an amount effective to provide
controlled release of the at least one opioid from the bead.
[0107] Pharmaceutical processing aids such as binders, diluents,
and the like may be included in the matrix bead formulations.
Amounts of these agents included in the formulations will vary with
the desired effect to be exhibited by the formulation.
[0108] The matrix beads may be overcoated with a controlled-release
coating including a controlled-release material such as those
described hereinabove. The controlled-release coating can be
applied to a weight gain of from about 5 to about 30%. The amount
of the controlled release coating to be applied will vary according
to a variety of factors, e.g., the composition of the matrix
beads.
[0109] Matrix beads are generally prepared by granulating the
spheronizing agent together with the agent, e.g. by wet
granulation. The granulate is then spheronized to produce the
matrix beads. The matrix beads are then optionally overcoated with
the controlled release coating by methods such as those described
hereinabove.
[0110] Another method for preparing matrix beads, for example, by
(a) forming granules comprising at least one water soluble
hydroxyalkyl cellulose and an opioid (b) mixing the hydroxyalkyl
cellulose containing granules with at least one C.sub.12-C.sub.36
aliphatic alcohol; and (c) optionally, compressing and shaping the
granules. Preferably, the granules are formed by wet granulating
the hydroxyalkyl cellulose/opioid with water.
[0111] In yet another alternative embodiment, spheronizing agent,
together with the active ingredient can be spheronized to form
spheroids. Microcrystalline cellulose is preferred. A suitable
microcrystalline cellulose is, for example, the material sold as
Avicel PH 101 (Trade mark, FMC Corporation). In such embodiments,
in addition to the active ingredient and spheronizing agent, the
spheroids may also contain a binder. Suitable binders, such as low
viscosity, water soluble polymers, will be well known to those
skilled in the pharmaceutical art. However, water soluble hydroxy
lower alkyl cellulose, such as hydroxy propyl cellulose, are
preferred. Additionally (or alternatively) the spheroids may
contain a water insoluble polymer, especially an acrylic polymer,
an acrylic copolymer, such as a methacrylic acid-ethyl acrylate
copolymer, or ethyl cellulose. In such embodiments, the
sustained-release coating will generally include a water insoluble
material such as (a) a wax, either alone or in admixture with a
fatty alcohol; or (b) shellac or zein.
[0112] In one especially preferred embodiment, the oral dosage form
comprises an effective number of controlled release spheroids
contained within a gelatin capsule.
[0113] In another preferred embodiment of the present invention,
the controlled-release dosage form comprises spheroids containing
the active ingredient coated with a controlled-release coating
including a controlled release material. The term spheroid is known
in the pharmaceutical art and means, e.g., a spherical granule
having a diameter of between 0.1 mm and 2.5 mm, or between 0.5 mm
and 2 mm. This range is not meant to be limiting as the diameter
can be higher or lower than disclosed above.
[0114] The spheroids are preferably film coated with a controlled
release material that permits release of the opioid at a controlled
rate in an aqueous medium. The film coat is chosen so as to
achieve, in combination with the other stated properties, the
desired in-vitro release rates The controlled-release coating
formulations of the present invention preferably produce a strong,
continuous film that is smooth and elegant, capable of supporting
pigments and other coating additives, non-toxic, inert, and
tack-free.
Sustained-Release Coating Formulations
[0115] The oral dosage forms of the present invention may
optionally be coated with one or more coatings suitable for the
regulation of release of for the protection of the formulation. In
one embodiment, coatings are provided to permit either pH-dependent
or pH-independent release, e.g., when exposed to gastrointestinal
fluid. When a pH-independent coating is desired, the coating is
designed to achieve optimal release regardless of pH-changes in the
environmental fluid, e.g., the GI tract, to avoid dose dumping.
Other preferred embodiments include a pH-dependent coating that
releases the at least one opioid antagonist in desired areas of the
gastro-intestinal (GI) tract, e.g., the stomach or small intestine.
It is also possible to formulate compositions which release a
portion of the dose in one desired area of the GI tract, e.g., the
stomach, and release the remainder of the dose in another area of
the GI tract, e.g., the small intestine.
[0116] Formulations according to the invention that utilize
pH-dependent coatings may also impart a repeat-action effect
whereby unprotected drug is coated over an enteric coat and is
released in the stomach, while the remainder, being protected by
the enteric coating, is released further down the gastrointestinal
tract. Coatings which are pH-dependent may be used in accordance
with the present invention include a controlled release material
such as, e.g., shellac, cellulose acetate phthalate (CAP),
polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose
phthalate, and methacrylic acid ester copolymers, zein, and the
like.
[0117] In another preferred embodiment, the present invention is
related to a stabilized solid controlled dosage form comprising the
opioid coated with a hydrophobic controlled release material
selected from (i) an alkylcellulose; (ii) an acrylic polymer; or
(iii) mixtures thereof. The coating may be applied in the form of
an organic or aqueous solution or dispersion.
[0118] In certain preferred embodiments, the controlled release
coating is derived from an aqueous dispersion of the hydrophobic
controlled release material. The coated substrate containing the
opioid (e.g., a tablet core or inert pharmaceutical beads or
spheroids) is then cured until an endpoint is reached at which the
substrate provides a stable dissolution. The curing endpoint may be
determined by comparing the dissolution profile (curve) of the
dosage form immediately after curing to the dissolution profile
(curve) of the dosage form after exposure to accelerated storage
conditions of, e.g., at least one month at a temperature of
40.degree. C. and a relative humidity of 75%. These formulations
are described in detail in U.S. Pat. Nos. 5,273,760 and 5,286,493.
Other examples of controlled-release formulations and coatings
which may be used in accordance with the present invention include
Assignee's U.S. Pat. Nos. 5,324,351, 5,356,467, and 5,472,712.
[0119] In preferred embodiments, the controlled release coatings
include a plasticizer such as those described herein below.
[0120] In certain embodiments, it is necessary to overcoat the
substrate comprising the opioid with a sufficient amount of the
aqueous dispersion of e.g., alkylcellulose or acrylic polymer, to
obtain a weight gain level from about 2 to about 50%, e.g., about 2
to about 25% in order to obtain a controlled-release formulation.
The overcoat may be lesser or greater depending upon the physical
properties of the therapeutically active agent and the desired
release rate, the inclusion of plasticizer in the aqueous
dispersions and the manner of incorporation of the same, for
example.
Alkylcellulose Polymers
[0121] Cellulosic materials and polymers, including alkylcelluloses
are controlled release materials well suited for coating the
substrates, e.g., beads, tablets, etc. according to the invention.
Simply by way of example, one preferred alkylcellulosic polymer is
ethylcellulose, although the artisan will appreciate that other
cellulose and/or part of a hydrophobic coatings according to the
invention.
[0122] One commercially-available aqueous dispersion of
ethylcellulose is Aquacoat.RTM. (FMC Corp., Philadelphia, Pa.,
U.S.A.). Aquacoat.RTM. is prepared by dissolving the ethylcellulose
in a water-immiscible organic solvent and then emulsifying the same
in water in the presence of a surfactant and a stabilizer. After
homogenisation to generate submicron droplets, the organic solvent
is evaporated under vacuum to form a pseudolatex. The plasticizer
is not incorporated in the pseudolatex during the manufacturing
phase. Thus, prior to using the same as a coating, it is necessary
to intimately mix the Aquacoat.RTM. with a suitable plasticizer
prior to use.
[0123] Another aqueous dispersion of ethylcellulose is commercially
available as Surelease.RTM. (Colorcon, Inc., West Point, Pa.,
U.S.A.). This product is prepared by incorporating plasticizer into
the dispersion during the manufacturing process. A hot melt of a
polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic
acid) is prepared as a homogeneous mixture, which is then diluted
with an alkaline solution to obtain an aqueous dispersion which can
be applied directly onto substrates.
Acrylic Polymers
[0124] In other preferred embodiments of the present invention, the
controlled release material comprising the controlled-release
coating is a pharmaceutically acceptable acrylic polymer, including
but not limited to acrylic acid and methyacrylic acid copolymers,
methyl methacrylate copolymers, ethoxyethyl methacrylates,
cynaoethyl methacrylate, poly(acrylic acid), poly(methacrylic
acid), methacrylic acid alkylamide copolymer, poly(methyl
methacrylate), polymethacrylate, poly(methyl methacrylate)
copolymer, polyacrylamide, aminoalkyl methacrylate copolymer,
poly(methacrylic acid anhydride) and glycidyl methacrylate
copolymers.
[0125] In certain preferred embodiments, the acrylic polymer is
comprised of one or more ammonio methacrylate copolymers. Ammonio
methacrylate copolymers are well known in the art, and are
described as fully polymerised copolymers of acrylic and
methacrylic acid esters with a low content of quaternary ammonium
groups.
[0126] In order to obtain a desirable dissolution profile, it may
be necessary to incorporate two or more ammonio methacrylate
copolymers having differing physical properties, such as different
molar ratios of the quaternary ammonium groups to the neutral
(meth)acrylic esters.
[0127] Certain methacrylic acid ester-type polymers are useful for
preparing pH-dependent coatings which may be used in accordance
with the present invention. For example, there are a family of
copolymers synthesized from diethylaminoethyl methacrylic acid
copolymer or polymeric methacrylates, commercially available as
Eudragit.RTM. from Rohm Tech, Inc. There are several different
types of Eudragit.RTM.. For example, Eudragit E is an example of a
methacrylic acid copolymer which does not swell at about pH<5.7
and is soluble at about pH>6. Eudragit S does not swell at about
pH<6.5 and is soluble at about pH>7. Eudragit RL and Eudragit
RS are water swellable, and the amount of water absorbed by these
polymers is pH-dependent, however, dosage forms coated with
Eudragit RL and RS are pH-independent.
[0128] In certain preferred embodiments, the acrylic coating
comprises a mixture of two acrylic resin lacquers commercially
available from Rohm Pharma under the Tradenames Eudragit.RTM. RL30D
and Eudragit.RTM. RS30D, respectively. Eudragit.RTM. RL30D and
Eudragit.RTM. RS30D are copolymers of acrylic and methacrylic
esters with a low content of quaternary ammonium groups, the molar
ratio of ammonium groups to the remaining neutral (meth)acrylic
esters being 1:20 in Eudragit.RTM. RL30D and 1:40 in Eudragit.RTM.
RS30D. The mean molecular weight is about 150,000. The code
designations RL (high permeability) and RS (low permeability) refer
to the permeability properties of these agents. Eudragit.RTM. RL/RS
mixtures are insoluble in water and in digestive fluids. However,
coatings formed from the same are swellable and permeable in
aqueous solutions and digestive fluids.
[0129] The Eudragit.RTM. RL/RS dispersions of the present invention
may be mixed together in any desired ration in order to ultimately
obtain a controlled-release formulation having a desirable
dissolution profile. Desirable controlled-release formulations may
be obtained, for instance, from a retardant coating derived from
100% Eudragit.RTM. RL, 50% Eudragit.RTM. RL and 50% Eudragit.RTM.
RS, and 10% Eudragit.RTM. RL: Eudragit.RTM. RS. Of course, one
skilled in the art will recognize that other acrylic polymers may
also be used, such as, for example, Eudragit.RTM. L.
Plasticizers
[0130] In embodiments of the present invention where the coating
comprises an aqueous dispersion of a hydrophobic controlled release
material, the inclusion of an effective amount of a plasticizer in
the aqueous dispersion of hydrophobic material will further improve
the physical properties of the controlled-release coating. For
example, because ethylcellulose has a relatively high glass
transition temperature and does not form flexible films under
normal coating conditions, it is preferable to incorporate a
plasticizer into an ethylcellulose coating containing
controlled-release coating before using the same as a coating
material. Generally, the amount of plasticizer included in a
coating solution is based on the concentration of the film-former,
e.g., most often from about 1 to about 50 percent by weight of the
film-former. Concentration of the plasticizer, however, can only be
properly determined after careful experimentation with the
particular coating solution and method of application.
[0131] Examples of suitable plasticizers for ethylcellulose include
water insoluble plasticizers such as dibutyl sebacate, diethyl
phthalate, triethyl citrate, tibutyl citrate, and triacetin,
although it is possible that other water-insoluble plasticizers
(such as acetylated monoglycerides, phthalate esters, castor oil,
etc.) may be used. Triethyl citrate is an especially preferred
plasticizer for the aqueous dispersions of ethyl cellulose of the
present invention.
[0132] Examples of suitable plasticizers for the acrylic polymers
of the present invention include, but are not limited to citric
acid esters such as triethyl citrate NF XVI, tributyl citrate,
dibutyl phthalate, and possibly 1,2-propylene glycol. Other
plasticizers which have proved to be suitable for enhancing the
elasticity of the films formed from acrylic films such as
Eudragit.RTM. RL/RS lacquer solutions include polyethylene glycols,
propylene glycol, diethyl phthalate, castor oil, and triacetin.
Triethyl citrate is an especially preferred plasticizer for the
aqueous dispersions of ethyl cellulose of the present
invention.
[0133] It has further been found that the addition of a small
amount of talc to the controlled release coating reduces the
tendency of the aqueous dispersion to stick during processing, and
act as a polishing agent.
Preparation of Coated Bead Formulations
[0134] When an aqueous dispersion of hydrophobic material is used
to coat substrates, e.g., inert pharmaceutical beads such as nu
pariel 18/20 beads, a plurality of the resultant stabilized solid
controlled-release beads may thereafter be places in a gelatin
capsule in an amount sufficient to provide an effective
controlled-release dose when ingested and contacted by an
environmental fluid, e.g., gastric fluid or dissolution media.
[0135] The stabilized controlled-release bead formulations of the
present invention slowly release the opioid antagonist, e.g., when
ingested and exposed to gastric fluids, and then to intestinal
fluids. The controlled-release profile of the formulations of the
invention can be altered, for example, by varying the amount of
overcoating with the aqueous dispersion of hydrophobic controlled
release material, altering the manner in which the plasticizer is
added to the aqueous dispersion of hydrophobic controlled release
material, by varying the amount of plasticizer relative to
hydrophobic controlled release material, by the inclusion of
additional ingredients or excipients, by altering the method of
manufacture, etc. The dissolution profile of the ultimate product
may also be modified, for example, by increasing or decreasing the
thickness of the controlled release coating.
[0136] Substrates coated with a therapeutically active agent are
prepared, e.g. by dissolving the therapeutically active agent in
water and then spraying the solution onto a substrate, for example,
nu pariel 18/20 beads, using a Wuster insert. Optionally,
additional ingredients are also added prior to coating the beads in
order to assist the binding of the opioid to the beads, and/or to
color the solution, etc. For example, a product which includes
hydroxypropyl methylcellulose, etc. with or without colorant (e.g.,
Opadry.RTM., commercially available from Colorcon, Inc.) may be
added to the solution and the solution mixed (e.g., for about 1
hour) prior to application of the same onto the substrate. The
resultant coated substrate may then be optionally overcoated with a
barrier agent, to separate the therapeutically active agent from
the hydrophobic controlled-release coating.
[0137] An example of a suitable barrier agent is one which
comprises hydroxypropyl methylcellulose. However, any film-former
known in the art may be used. It is preferred that the barrier
agent does not affect the dissolution rate of the final
product.
[0138] The substrates may then be overcoated with an aqueous
dispersion of the hydrophobic controlled release material. The
aqueous dispersion of hydrophobic controlled release material
preferably further includes an effective amount of plasticizer,
e.g. triethyl citrate. Pre-formulated aqueous dispersions of
ethylcellulose, such as Aquacoat.RTM. or Surelease.RTM., may be
used. If Surelease.RTM. is used, it is not necessary to separately
add a plasticizer. Alternatively, pre-formulated aqueous
dispersions of acrylic polymers such as Eudragit.RTM. can be
used.
[0139] The coating solutions of the present invention preferably
contain, in addition to the film-former, plasticizer, and solvent
system (i.e., water) a colorant to provide elegance and product
distinction. Color may be added to the solution of the
therapeutically active agent instead, or in addition to the aqueous
dispersion of hydrophobic material. For example, color can be added
to Aquacoat.RTM. via the use of alcohol or propylene glycol based
color dispersions, milled aluminium lakes and opacifiers such as
titanium dioxide by adding color with shear to water soluble
polymer solution and then using low shear to the plasticized
Aquacoat.RTM.. Alternatively, any suitable method of providing
color to the formulations of the present invention may be used.
Suitable ingredients for providing color to the formulation when an
aqueous dispersion of an acrylic polymer is used include titanium
dioxide and color pigments, such as iron oxide pigments. The
incorporation of pigments, may, however, increase the retard effect
of the coating.
[0140] The plasticized aqueous dispersion of hydrophobic controlled
release material may be applied onto the substrate comprising the
therapeutically active agent by spraying using any suitable spray
equipment known in the art. In a preferred method, a Wurster
fluidized-bed system is used in which an air jet, injected from
underneath fluidizes the core material and effects drying while the
acrylic polymer coating is sprayed on. A sufficient amount of the
aqueous dispersion of hydrophobic material to obtain a
predetermined controlled-release of said therapeutically active
agent when said coated substrate is exposed to aqueous solutions,
e.g. gastric fluid, is preferably applied, taking into account the
physical characteristics of the therapeutically active agent, the
manner of incorporation of the plasticizer, etc. After coating with
the hydrophobic controlled release material, a further overcoat of
a film-former, such as Opadry.RTM., is optionally applied to the
beads. This overcoat is provided, if at all, in order to
substantially reduce agglomeration of the beads.
[0141] The release of the therapeutically active agent from the
controlled-release formulation of the present invention can be
further influenced, i.e., adjusted to a desired rate, by the
addition of one or more release-modifying agents, or by providing
one or more passageways through the coating. The ratio of
hydrophobic controlled release material to water soluble material
is determined by, among other factors, the release rate required
and the solubility characteristics of the materials selected.
[0142] The release-modifying agents which function as pore-formers
may be organic or inorganic, and include materials that can be
dissolved, extracted or leached form the coating in the environment
of use. The pore-formers may comprise one or more hydrophilic
materials such as hydroxypropylmethylcellulose.
[0143] The controlled-release coatings of the present invention can
also include erosion-promoting agents such as starch and gums.
[0144] The controlled-release coatings of the present invention can
also include materials useful for making microporous lamina in the
environment of use, such as polycarbonates comprised of linear
polyesters of carbonic acid in which carbonate groups reoccur in
the polymer chain.
[0145] The release-modifying agent may also comprise a
semi-permeable polymer. In certain preferred embodiments, the
release-modifying agent is selected from
hydroxypropylmethylcellulose, lactose, metal stearates, and
mixtures of any of the foregoing.
[0146] The controlled-release coatings of the present invention may
also include an exit means comprising at least one passageway,
orifice, or the like. The passageway may be formed by such methods
as those disclosed in U.S. Pat. Nos. 3,845,770; 3,916,889;
4,063,064; and 4,088,864. The passageway can have any shape such as
round, triangular, square, elliptical, irregular, etc.
[0147] Another method of producing controlled release bead
formulations suitable for about 24-hour administration is via
powder layering. U.S. Pat. No. 5,411,745 teaches preparation of
24-hour morphine formulations prepared via powder layering
techniques utilizing a processing aid consisting essentially of
hydrous lactose impalpable. The powder-layered beads are prepared
by spraying an aqueous binder solution onto inert beads to provide
a tacky surface, and subsequently spraying a powder that is a
homogenous mixture of morphine sulfate and hydrous lactose
impalpable onto the tacky beads. The beads are then dried and
coated with a hydrophobic material such as those described
hereinabove to obtain the desired release of drug when the final
formulation is exposed to environmental fluids. An appropriate
amount of the controlled release beads are then, e.g. encapsulated
to provide a final dosage form which provides effective plasma
concentrations of morphine for about 24 hours.
Sustained Release Osmotic Dosage
[0148] Sustained release dosage forms according to the present
invention may also be prepared as osmotic dosage formulations. The
osmotic dosage forms preferably include a bilayer core comprising a
drug layer and a delivery or push layer, wherein the bilayer core
is surrounded by a semipermeable wall and optionally having at
least one passageway disposed therein.
[0149] The expression "passageway" as used for the purpose of this
invention, includes aperture, orifice, bore, pore, porous element
through which the at least one opioid can be pumped, diffuse or
migrate through a fiber, capillary tube, porous overlay, porous
insert, microporous member, or porous composition. The passageway
can also include a compound that erodes or is leached from the wall
in the fluid environment of use to produce at least one passageway.
Representative compounds for forming a passageway include erodible
poly(glycolic) acid, or poly(lactic) acid in the wall; a gelatinous
filament; a water-removable poly(vinyl alcohol); leachable
compounds such as fluid-removable pore-forming polysaccharides,
acids, salts or oxides. A passageway can be formed by leaching a
compound from the wall, such as sorbitol, sucrose, lactose,
maltose, or fructose, to form a sustained-release dimensional
pore-passageway. The passageway can have any shape, such as round,
triangular, square and elliptical, for assisting in the sustained
metered release of the at least one opioid from the dosage form.
The dosage form can be manufactured with one or more passageway in
spaced-apart relation on one or more surfaces of the dosage form. A
passageway and equipment for forming a passageway are disclosed in
U.S. Pat. Nos. 3,845,770; 3,916,899; 4,063,064 and 4,088,864.
passageways comprising sustained-release dimensions sized, shaped
and adapted as a releasing-pore formed by aqueous leaching to
procide a releasing-pore of a sustained-release rate are disclosed
in U.S. Pat. Nos. 4,200,098 and 4,285,987.
[0150] In certain embodiments, the bilayer core comprises a drug
layer with the opioid and a displacement or push layer. In certain
embodiments the drug layer may also comprise at least one polymer
hydrogel. The polymerhydrogel may have an average molecular weight
of between about 500 and about 6,000,000. Examples of polymer
hydrogels include but are not limited to a maltodextrin polymer
comprising the formula (C.sub.6H.sub.12O.sub.5).sub.n.H.sub.2O,
wherein n is 3 to 7,500, and the maltodextrin polymer comprises a
500 to 1,250,000 number-average molecular weight; a poly(alkylene
oxide) represented by, e.g., a poly(ethylene oxide) and a
polypropylene oxide) having a 50,000 to 750000 weight-average
molecular weight, and more specifically represented by a
poly(ethylene oxide) of at least one of 100,000, 200,000, 300,000
or 400,000 weight-average molecular weights; an alkali
carboxyalkylcellulose, wherein the alkali is sodium or potassium,
the alkyl is methyl, ethyl, propyl, or butyl of 10,000 to 175,000
weight-average molecular weight; and a copolymer of
ethylene-acrylic acid, including methacrylic and ethacrylic acid of
10,000 to 500,000 number-average molecular weight.
[0151] In certain embodiments of the present invention, the
delivery or push layer comprises an osmopolymer. Examples of an
osmopolymer include but are not limited to a member selected from
the group consisting of a polyalkylene oxide and a
carboxyalkylcellulose. The polyalkylene oxide possesses a 1,000,000
to 10,000,000 weight-average molecular weight. The polyalkylene
oxide may be a member selected form the group consisting of
polymethylene oxide, polyethylene oxide, polypropylene oxide,
comprising a 5,000,000 average molecular weight, polyethylene oxide
comprising a 7,000,000 average molecular weight, cross-linked
polymethylene oxide possessing a 1,000,000 average molecular
weight, and polypropylene oxide of 1,200,000 average molecular
weight. Typical osmopolymer carboxyalkylcellulose comprises a
member selected from the group consisting of alkali
carboxyalkylcellulose, sodium carboxymethylcellulose, potassium
carboxymethylcellulose, sodium carboxyethylcellulose, lithium
carboxymethylcellulose, sodium carboxyethylcellulose,
carboxyalkylhydroxyalkylcellulose, carboxymethylhydroxyethyl
cellulose, carboxyethylhydroxyethylcellulose and
carboxymethylhydroxypropylcellulose. The osmopolymers used for the
displacement layer exhibit an osmotic pressure gradient across the
semipermeable wall. The osmopolymers imbibe fluid into dosage form,
thereby swelling and expanding as an osmotic hacrogel (also known
as osmogel), whereby they push the opioid from the osmotic dosage
form.
[0152] The push layer may also include one or more osmotically
effective compounds also known as osmagents and as osmotically
effective solutes. They imbibe an environmental fluid, for example,
form the gastrointestinal tract, into dosage form and contribute to
the delivery kinetics of the displacement layer. Examples of
osmotically active compounds comprise a member selected form the
group consisting of osmotic salts and osmotic carbohydrates.
Examples of specific osmagents include but are not limited to
sodium chloride, potassium chloride, magnesium sulphate, lithium
phosphate, lithium chloride, sodium phosphate, potassium sulphate,
potassium phosphate, glucose, fructose and maltose.
[0153] The push layer may optionally include a
hydroxypropylalkylcellulose possessing a 9,000 to 450,000
number-average molecular weight. The hydroxypropylalkylcellulose is
represented by a member selected from the group consisting of
hydroxypropylmethylcellulose, hydroxypropylethylcellulose,
hydroxypropylisopropylcellulose, hydroxypropylbutylcellulose and
hydroxypropylpentylcellulose.
[0154] The push layer optionally may comprise a non-toxic colorant
or dye. Examples of colorants or dyes include but are not limited
to Food and Drug Administration Colorant (FD&C), such as
FD&C No. 1 blue dye, FD&C No. 4 red dye, red ferric oxide,
yellow ferric oxide, titanium dioxide, carbon black, and
indigo.
[0155] The push layer may also optionally comprise an antioxidant
to inhibit the oxidation of ingredients. Some examples of
antioxidants include but are not limited to a member selected from
the group consisting of ascorbic acid, ascorbyl palmitate,
butylated hydroxyanisole, a mixture of 2 and 3
tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodium
isoascorbate, dihydroguaretic acid, potassium sorbate, sodium
bisulphate, sodium meta bisulphate, sorbic acid, potassium
ascorbate, vitamin E, 4-chloro-2,6-ditertiary butylphenol, alpha
tocopherol, and propylgallate.
[0156] In certain alternative embodiments, the dosage form
comprises a homogenous core comprising the opioid, a
pharmaceutically acceptable polymer (e.g., polyethylene oxide),
optionally a disintegrant (e.g., polyvinylpyrrolidone), optionally
an absorption enhancer (e.g., a fatty acid, a surfactant, a
chelating agent, a bile salt, etc.). The homogenous core is
surrounded by a semipermeable wall having a passageway (as defined
above) for the release of the opioid.
[0157] In certain embodiments, the semipermeable wall comprises a
member selected from the group consisting of a cellulose ester
polymer, a cellulose ether polymer and a cellulose ester-ether
polymer. Representative wall polymers comprise a member selected
from the group consisting of cellulose acrylate, cellulose
diacylate, cellulose triacylate, cellulose acetate, cellulose
diacetate, cellulose triacetate, mono-, di- and tricellulose
alkenylates, and mono-, di and tricellulose alkinylates. The
poly(cellulose) used for the present invention comprises a
number-average molecular weight of 20,000 to 7,500,000.
[0158] Additional sempermeable polymers for the purpose of this
invention comprise acetaldehyde dimethylcellulose acetate,
cellulose acetate ethylcarbamate, cellulose acetate
methylcarbamate, cellulose diacetate, propylcarbamate, cellulose
acetate diethylaminoacetate; semipermeable polyamide; semipermeable
polyurethane; semipermeable sulfonated polystyrene; semipermeable
cross-linked polymer formed by the coprecipitation of a polyanion
and a polycation as disclosed in U.S. Pat. Nos. 3,173,876;
3,276,586; 3,541,005; 3,541,006 and 3,546,876; semipermeable
polymers as disclosed by Loeb and Sourirajan in U.S. Pat. No.
3,133,132; semipermeable crosslinked polystyrenes; semipermeable
crosslinked (poly(sodium styrene sulfonate); semipermeable
crosslinked poly(vinylbenzyltrimethyl ammonium chloride); and
semipermeable polymers possessing a fluid permeability of
2.5.times.10.sup.-8 to 2.5.times.10.sup.-2 (cm.sup.2/hratm)
expressed per atmosphere of hydrostatic or osmotic pressure
difference across the semipermeable wall. Other polymers useful in
the present invention are known in the art in U.S. Pat. Nos.
3,845,770; 3,916,899 and 4,160,020); and in Handbook of Common
Polymers, Scott, J. R. and W. J. Roff, 1971, CRC Press, Cleveland,
Ohio.
[0159] In certain embodiments, preferably the semipermeable wall is
non-toxic, inert, and it maintains its physical and chemical
integrity during the dispensing life of the drug. In certain
embodiments, the dosage form comprises a binder. An example of a
binder includes, but is not limited to a therapeutically acceptable
vinyl polymer having a 5,000 to 350,000 viscosity-average molecular
weight, represented by a member selected from the group consisting
of poly-n-vinylamide, poly-n-vinylacetamide,
poly(vinylpyrrolidone), also known as poly-n-vinylpyrrolidone),
poly-n-vinylcaprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, and
poly-n-vinyl-pyrrolidone copolymers with a member selected from the
group consisting of vinyl acetate, vinyl alcohol, vinyl chloride,
vinyl fluoride, vinyl butyrate, vinyl laureate, and vinyl stearate.
Other binders include for example, acacia, starch, gelatin, and
hydroxypropylalkylcellulose of 9,200 to 250,000 average molecular
weight.
[0160] In certain embodiments, the dosage form comprises a
lubricant, which may be used during the manufacture of the dosage
form to prevent sticking to die wall or puch faces. Examples of
lubricants include but are not limited to magnesium stearate,
sodium stearate, stearic acid, calcium stearate, magnesium oleate,
oleic acid, potassium oleate, carprylic acid, sodium stearyl
fumarate, and magnesium palmitate.
[0161] In certain preferred embodiments, the present invention
includes a therapeutic composition comprising 1 to 640 mg of the
opioid, 25 to 500 mg of poly(alkylene oxide) having a 150,000 to
500,000 average molecular weight 1 to 50 mg of
poly(vinylpyrrolidone) having a 40,000 average molecular weight,
and 0 to about 7.5 mg of a lubricant.
[0162] In certain embodiments, the invention also provides a method
for administering at least one opioid by admitting orally a dosage
form comprising 1 to 640 mg of opioid, a semipermeable wall
permeable to aqueous-biological fluid and impervious to the
passageway of the opioid which semipermeable wall surrounds an
internal space comprising the opioid composition and a push
composition, the opioid composition comprising 1 to 640 mg of
opioid, 25 to 500 mg of a poly(alkylene oxide) having a 150,000 to
500,000 average molecular weight, 1 to 50 mg of a
poly(vinylpyrrolidone) having a 40,000 average molecular weight,
and 0 to 7.5 mg of a lubricant, said push composition comprising 15
to 250 mg of a poly(alkylene oxide) of 3,000,000 to 7,500,000
average molecular weight, 0 to 75 mg of an osmagent, 1 to 50 mg of
a hydroxyalkylcellulose, 0 to 10 mg of ferric oxide, 0 to 10 mg of
a lubricant, and 0 to 10 mg of antioxidant; and a passageway in the
imbibing fluid through the semipermeable wall into the dosage form
causing the opioid composition to become dispensable and the push
composition to expand and push the opioid composition through the
passageway, whereby through the combined operations of the dosage
form, the opioid is delivered at a therapeutically effective dose
at a rate controlled over a sustained period of time.
[0163] The dosage forms of the present invention may optionally be
coated with one or more coating suitable for the regulation of
release or for the protection of the formulation. In one
embodiment, coatings are provided to permit either pH-dependent or
pH-independent release, e.g., when exposed to gastrointestinal (GI)
fluid. When a pH-independent coating is desired, the coating is
designed to achieve optimal release regardless of pH-changes in the
environmental fluid, e.g., the GI tract. Other preferred
embodiments include a pH-dependent coating that releases the opioid
in desired areas of the GI tract, e.g., the stomach or small
intestine, such that an absorption profile is provided which is
capable of providing at least about twelve hours and preferably
about twenty-four hours or more of a therapeutical effect to a
patient. It is also possible to formulate compositions which
release a portion of the dose in one desired area of the GI tract,
e.g., the stomach, and release the remainder of the dose in another
area of the GI tract, e.g., the small intestine.
[0164] Formulations according to the invention that utilize
pH-dependent coatings may also impart a repeat-action effect
whereby unprotected drug is coated over an enteric coat and is
released in the stomach, while the remainder, being protected by
the enteric coating, is released further down the gastrointestinal
tract. Coatings which are pH-dependent and may be used in
accordance with the present invention include a sustained release
material such as, e.g., shellac, cellulose acetate phthalate (CAP),
polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose
phthalate, and methacrylic acid ester copolymers, zein, and the
like.
[0165] In certain embodiments of the present invention, an
effective amount of an opioid in immediate release form is included
in the formulation. By including such an effective amount of
immediate release opioid in the unit dose. In such embodiments, an
effective amount of the opioid in immediate release form may be
coated onto the tablet of the present invention. For example, where
the extended release of the opioid from the formulation is due to a
sustained release coating, the immediate release layer would be
overcoated on top of the sustained release coating. On the other
hand, the immediate release layer may be coated onto the surface of
tablets wherein the opioid is incorporated in a sustained release
matrix. One skilled in the art would recognize still other
alternative manners of incorporating the immediate release opioid
portion into the formulation. Such alternatives are deemed to be
encompassed by the appended claims.
[0166] The following examples illustrate some preferred
preparations. They are not to be construed to limit the claims in
any manner whatsoever.
Example 1
Production of Tablets with Different Oxycodone/Naloxone Amounts in
a Non-Swellable Diffusion Matrix by Spray Granulation
[0167] The following amounts of the listed components were used for
the production of oxycodone/naloxone tablets according to the
invention.
TABLE-US-00001 Preparation (designation) Oxy/Nal-0 Oxy/Nal-5
Oxy/Nal-10 oxycodone HCl 20.0 mg 20.0 mg 20.0 mg naloxone HCl --
5.0 mg 10.0 mg Lactose Flow Lac 100 59.25 mg 54.25 mg 49.25 mg
Povidone 30 5.0 mg 5.0 mg 5.0 mg Surelease .RTM. 10.0 mg 10.0 mg
10.0 mg solid material solid material solid material Stearyl
alcohol 25.0 mg 25.0 mg 25.0 mg Talcum 2.5 mg 2.5 mg 2.5 mg
Mg-Stearate 1.25 mg 1.25 mg 1.25 mg
[0168] The Surelease.RTM. E-7-7050 polymer mixture used had the
following composition.
[0169] Surelease.RTM.
[0170] Ethylcellulose 20 cps
[0171] Dibutylsebacate
[0172] Ammoniumhydroxide
[0173] Oleic acid
[0174] Siliciumdioxide
[0175] Water
[0176] For the production of tablets oxycodone HCl, naloxone HCl,
Povidone 30 and Lactose Flow Lac 100 were mixed in a tumbling mixer
(Bohle) and subsequently spray-granulated with Surelease.RTM.
E-7-7050 in a fluidized bath granulating device (GPCG3). The
material was sieved over a Comill 1.4 mm sieve. An additional
granulation step was carried out with melted fatty alcohol in a
high-shear mixer (Collette). All tablet cores produced by this
approach had a weight of 123 mg, based on dry substance.
Example 2
Production of Tablets with Oxycodone and Naloxone in a
Non-Swellable Diffusion Matrix by Extrusion
[0177] The following amounts of the listed components were used for
the production of the oxycodone/naloxone tablets according to the
invention.
TABLE-US-00002 Preparation (designation) Oxy/Nal-Extr oxycodone HCl
20 mg naloxone HCl 10 mg Kollidon 30 6 mg Lactose Flow Lac 100
49.25 mg Ethylcellulose 45 cpi 10 mg Stearyl alcohol 24 mg Talcum
2.5 mg Mg-Stearate 1.25 mg
[0178] The listed amounts of oxycodone HCl, naloxone HCl,
ethylcellulose 45 cps, Povidone 30, stearyl alcohol and Lactose
Flow Lac 100 were mixed in a tumbling mixer (Bohle). This mixture
was subsequently extruded with a counter-rotating twin screw
extruder of the type Micro 18 GGL (Leistritz AG, Nurnberg,
Germany). The temperature of heating zone 1 was 25.degree. C., of
heating zone 2, 50.degree. C., of heating zones 3 to 5, 60.degree.
C., of heating zones 6 to 8, 55.degree. C., of heating zone 9,
60.degree. C. and of heating zone 10, 65.degree. C. The screw
rotating speed was 150 revolutions per minute (rpm), the resulting
melt temperature was 87.degree. C., the feed rate was 1.5 kg/h and
the diameter of the nozzle opening was 3 mm. The extruded material
was sieved with a Frewitt 0.68.times.1.00 mm sieve. The grinded
extrudate was then mixed with talcum and magnesium stearate that
had been added over a 1 mm hand sieve and was subsequently pressed
into tablets.
[0179] In comparison to the oxycodone/naloxone tablets which also
have the Surelease.RTM.-based non-swellable diffusion matrix
produced by spray granulation (see Example 1), extruded
preparations comprise less components.
Example 3
Release Profile of the Oxycodone/Naloxone Tablets from Example
1
[0180] The release of the active compounds was measured over a time
period of 12 hours, applying the Basket Method according to USP at
pH 1.2 using HPLC. Tablets Ox/Nal-0, Ox/Nal-5 and Ox/Nal-10 were
tested.
[0181] One recognizes from the table that in the case of a
non-swellable diffusion matrix based on Surelease.RTM., the release
rates of different oxycodone amounts, independent of the naloxone
amount, remain equal (invariant). Correspondingly, invariant
release profiles are observed for naloxone at different oxycodone
amounts.
TABLE-US-00003 Ox/ Ox/ Ox/ Ox/ Ox/ Time Nal-0 Nal-5-O Nal-5-N
Nal-10-O Nal-10-N (min) Oxy Oxy Nal Oxy Nal 0 0 0 0 0 0 15 26.1
24.9 23.5 22.8 24.1 120 62.1 63 61 57.5 60.2 420 91.7 94.5 91.9
89.4 93.5 720 98.1 99.6 96.6 95.7 100.6
[0182] The release values refer to oxycodone or naloxone (line 2)
and are given as percentages. The mean value for the release of
naloxone at e.g. 420 min is 92.7%.
[0183] The maximal deviation at 420 min is 1%. Oxy and Nal stand
for oxycodone and naloxone and indicate the active compound which
has been measured.
Example 4
Release Profile of Oxycodone/Naloxone Tablets from Example 2 at
Different pH-Values
[0184] The release of active compounds from the tablets was
measured over a time period of 12 hours at pH 1.2 or for 1 hour at
1.2 and subsequently for 11 hours at pH 6.5. Release rates were
determined by the basket method according to USP using HPLC.
[0185] The following release rates were measured for 12 hours at pH
1.2:
TABLE-US-00004 Time Oxy/Nal-Extr-1,2-O Oxy/Nal-Extr-1,2-N (min) Oxy
Nal 0 0 0 15 24.1 24.0 120 62.9 63.5 420 92.9 93.9 720 96.9
98.1
[0186] The following release rates were measured for 1 hour at pH
1.2 and 11 hours at pH 6.5:
TABLE-US-00005 Time Oxy/Nal-Extr-6,5-O Oxy/Nal-Extr-6,5-N (min) Oxy
Nal 0 0 0 60 48.1 49.2 120 65.0 64.7 240 83.3 81.8 420 94.1
92.3
[0187] The release rates refer to oxycodone and naloxone (line 2)
and are given as percentages. Oxy and Nal stand for oxycodone and
naloxone and indicate the active compound measured.
[0188] Further suitable examples with a combination of oxycodone as
agonist and naloxone as antagonist are disclosed in PCT/EP
03/03541.
Examples 5 and 6
Controlled Release Oxycodone Formulations, 10 and 20 mg Tablets
[0189] Eudragite.RTM. RS 30D and Triacetine are combined while
passing though a 60 mesh screen, and mixed under low shear for
approximately 5 minutes or until a uniform dispersion is
observed.
[0190] Next, suitable quantities of Oxycodone HCl, lactose, and
povidone are placed into a fluid bed granulator/dryer (FBD) bowl,
and the suspension sprayed onto the powder in the fluid bed. After
spraying, the granulation is passed through a #12 screen if
necessary to reduce lumps. The dry granulation is placed in a
mixer.
[0191] In the meantime, the required amount of stearyl alcohol is
melted at a temperature of approximately 70.degree. C. The melted
stearyl alcohol is incorporated into the granulation while mixing.
The waxed granulation is transferred to a fluid bed
granulator/dryer or trays and allowed to cool to room temperature
or below. The cooled granulation is then passed through a #12
screen. Thereafter, the waxed granulation is placed in a
mixer/blender and lubricated with the required amounts of talc and
magnesium stearate for approximately 3 minutes, and then the
granulate is compressed into 125 mg tablets on a suitable tableting
machine.
[0192] The formula for the tablets of Example 5 (10 mg tablet) is
set forth in the table below:
TABLE-US-00006 Component Mg/Tablet % (by wt) Oxycodone
Hydrochloride 10.0 8.0 Lactose (spray dried) 69.25 55.4 Povidone
5.0 4.0 Eudragit .RTM. RS 30D (solids) 10.0* 8.0 Triacetin .RTM.
2.0 1.6 Stearyl Alcohol 25.0 20.0 Talc 2.5 2.0 Magnesium Stearate
1.25 1.0 Total: 125.0 100.0 *Approximately 33.33 mg Eudragit .RTM.
RS 30D Aqueous dispersion is equivalent to 10 mg of Eudragit .RTM.
RS 30D dry substance.
[0193] The formula for the tablets of Example 6 (20 mg tablet) is
set forth in the table below:
TABLE-US-00007 Component Mg/Tablet Oxycodone Hydrochloride 20.0
Lactose (spray dried) 59.25 Povidone 5.0 Eudragit .RTM. RS 30D
(solids) 10.0* Triacetin .RTM. 2.0 Stearyl Alcohol 25.0 Talc 2.5
Magnesium Stearate 1.25 Total: 125.0
Example 7
[0194] The tablets of Example 5 are then tested for dissolution via
the USP Basket Method at 37.degree. C., 100 RPM, first hour 700 ml
simulated gastric fluid at pH 1.2, then changed to 900 ml at pH
7.5. The results are set forth in the table below:
TABLE-US-00008 Time % Oxycodone (hours) Dissolved 1 38.0 2 47.5 4
62.0 8 79.8 12 91.1 18 94.9 24 98.7
Example 8
[0195] The tablets of Example 6 are then tested for dissolution via
the USP Basket Method at 3.degree. C., 100 RPM, first hour 700 ml
simulated gastric fluid at pH 1.2, then changed to 900 ml at pH
7.5. The results are set forth in the table below:
TABLE-US-00009 Time % Oxycodone (hours) Dissolved 1 31 2 44 4 57 8
71 12 79 18 86 24 89
[0196] Further suitable examples with oxycodone as agonist and
corresponding in vivo data are disclosed in EP 0 576 643
(incorporated herein by reference).
Example 9
[0197] 24 hour 160 mg oxycodone sustained release capsules were
prepared with the formula set forth in table below:
TABLE-US-00010 Component Mg/unit Oxycodone HCL 160 Stearic Acid 80
Stearyl Alcohol 20 Eudragit RSPO 140 Total 400
[0198] The formulation above was prepared according to the
following procedure:
[0199] 1. Pass the stearyl alcohol flakes through an impact
mill.
[0200] 2. Blend the Oxycodone HCl, stearic acid, stearyl alcohol
and the Eudragit RSPO in a suitable lender/mixer.
[0201] 3. Continuously feed the blended material into a twin screw
extruder at elevated temperatures and collect the resultant strands
on a conveyor.
[0202] 4. Allow the strands to cool on the conveyor.
[0203] 5. Cut the strands into 1 mm pellets using a pelletizer.
[0204] 6. Screen the pellets for fines and oversized pellets to an
acceptable range of about 0.8
[0205] 1.4 mm in size.
[0206] 7. Fill into capsules with a fill weight of 400 mg/capsule
(Fill into size 00 capsules).
Example 10
[0207] The tablets of Example 9 are then tested for dissolution The
pellets were then using the following procedure:
[0208] Fiber optic UV dissolution using USP apparatus 1 (basket) at
100 rpm in 900 ml simulated gastric fluid (SGF) and in 900 ml
simulated intestinal fluid (SIF) monitoring at
282 nm.
[0209] The dissolution parameters for the above formulation are set
forth in Table below:
TABLE-US-00011 Time % Dissolved % Dissolved (hour) in SGF in SIF 1
32 20 2 47 28 4 66 42 8 86 60 12 93 70 18 95 77 24 95 80
Clinical Studies
[0210] Example 11 is a multicenter, randomized, placebo controlled
double blind parallel group study. The study was conducted on 7
male and female COPD emphysematous patients at stage II or III (ATS
staging) of the pink puffer stereotype at the age from 54 to 76
years.
[0211] 4 patients were treated with Oxygesic.RTM. (Oxycodon
twice-a-day oral controlled release dosage form) and 3 patients
received placebo. The effect of oral controlled release oxycodone
on the tolerance with regard to physiological strain and dyspnea
was determined.
[0212] The tolerance with regard to physiological strain was rated
by determining the average distance covered in 6 minutes at 0.7 and
42 days after the start of treatment. The results are set forth in
the table below:
[0213] Average distance (m) covered in 6 minutes:
TABLE-US-00012 Treatment Oxygesic (n = 4) Placebo (n = 3) day 0
178.8 238.3 day 7 188.8 215.0 day 42 260.0 225.0 absolute change
(m) +80.2 -13.3 relative change (%) +44.9% -4.7%
[0214] Dyspnea was rated on a scale from -3 to +3 (-3=noticeable
declined, -2=declined, -1=slightly declined, 0=no change,
+1=slightly improved, +2=improved, +3=noticeable improved). The
results from the case report form are set forth in the table
below.
[0215] Dyspnea rating from the case report form:
TABLE-US-00013 Treatment Oxygesic (n = 4) Placebo (n = 3) day 4 0.5
-0.3 day 7 1.0 -0.5 first telephone contact 1.7 -0.5 second
telephone 1.7 -1.5 contact
[0216] Dyspnea rating on a scale out of 0 to 10 (0=no dyspnea to
10=most imaginable dyspnea) over a treatment period of 14 days from
the patient diary are summarized in FIG. 1.
[0217] The overall efficacy was rated by the patient and
investigator to be 2.8 and 2.5, respectively, with respect to the
treatment with Oxygesic.RTM. and 5.0 and 3.7, respectively, with
respect to the placebo treatment, on a scale out of 1 to 7 (1=very
good, 7=very bad). The patient compliance was generally good.
* * * * *