U.S. patent application number 10/510674 was filed with the patent office on 2005-11-03 for pharmaceutical preparation containing oxycodone and naloxone.
Invention is credited to Brogmann, Bianca, Muhlau, Silke, Spitzley, Christof.
Application Number | 20050245556 10/510674 |
Document ID | / |
Family ID | 28676052 |
Filed Date | 2005-11-03 |
United States Patent
Application |
20050245556 |
Kind Code |
A1 |
Brogmann, Bianca ; et
al. |
November 3, 2005 |
Pharmaceutical preparation containing oxycodone and naloxone
Abstract
The invention concerns a storage stable pharmaceutical
preparation comprising oxycodone and naloxone for use in pain
therapy with the active compounds being released from the
preparation in a sustained, invariant and independent manner.
Inventors: |
Brogmann, Bianca; (Ulm,
DE) ; Muhlau, Silke; (Diez, DE) ; Spitzley,
Christof; (Elbtal-Heuchelheim, DE) |
Correspondence
Address: |
Jones Day
222 East 41st Street
New York
NY
10017
US
|
Family ID: |
28676052 |
Appl. No.: |
10/510674 |
Filed: |
May 23, 2005 |
PCT Filed: |
April 4, 2003 |
PCT NO: |
PCT/EP03/03540 |
Current U.S.
Class: |
514/282 |
Current CPC
Class: |
Y10S 514/812 20130101;
A61K 9/0053 20130101; A61K 9/1652 20130101; A61K 9/2009 20130101;
A61K 9/2866 20130101; A61P 43/00 20180101; A61K 9/1617 20130101;
A61K 9/2013 20130101; A61K 9/2054 20130101; A61P 29/00 20180101;
A61K 9/2095 20130101; A61P 17/04 20180101; Y10S 514/81 20130101;
A61P 13/12 20180101; A61P 1/00 20180101; A61P 1/04 20180101; A61P
1/10 20180101; A61K 9/2018 20130101; A61K 9/2077 20130101; A61P
25/36 20180101; A61K 9/70 20130101; A61K 31/485 20130101; A61P
25/00 20180101; A61P 25/04 20180101; A61K 31/485 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/282 |
International
Class: |
A61K 031/485 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 5, 2002 |
DE |
102 15 131.8 |
Apr 5, 2002 |
DE |
102 15 067.2 |
Claims
1. A storage stable pharmaceutical preparation comprising oxycodone
and naloxone in a substantially non-swellable diffusion matrix
comprising ethyl cellulose, characterized in that the active
compounds are released from the preparation in a sustained,
invariant and independent manner.
2. Preparation according to claim 1, characterized in that
oxycodone and/or naloxone are present in the form of
pharmaceutically acceptable and equally active derivatives such as
the free base, salts and the like.
3. Preparation according to claim 2, characterized in that
oxycodone and/or naloxone are present as their hydrochloride,
sulfate, bisulfate, tatrate, nitrate, citrate, bitatrate,
phosphate, malate, maleate, hydrobromide, hydroiodide, fumarate or
succinate.
4. Preparation according to claim 3, characterized in that
oxycodone is present in excess referred to the unit dosage amount
of naloxone.
5. Preparation according to claim 1, characterized in that naloxone
is present in an amount range of about 1 g to about 50 mg.
6. Preparation according to claim 1, characterized in that
oxycodone is present in an amount range of about 10 mg to about 150
mg.
7. Preparation according to claim 1, characterized in that
oxycodone and naloxone are present in weight ratio ranges of from
about 25:1 to about 1:1.
8. Preparation according to claim 7, characterized in that the
preparation comprises a substantially non-erosive diffusion
matrix.
9. Preparation according to claim 8, characterized in that the
diffusion matrix comprises at least ethylcellulose and at least one
fatty alcohol as the components that essentially influence the
release behavior of the active compounds.
10. Preparation according to claim 9, characterized in that the
preparation does not comprise relevant parts of alkaline and/or
water-swellable substance.
11. Preparation according to claim 10, characterized in that the
preparation contains fillers and additional substances.
12. Preparation according to claim 11, characterized in that it
comprises magnesium stearate, calcium stearate and/or calcium
laureate and/or fatty acids.
13. Preparation according to claim 11, characterized in that it
comprises a flowing agent selected from the group consisting of
highly-disperse silica, talcum, corn starch, magnesium oxide and
magnesium and calcium stearate.
14. A storage stable pharmaceutical preparation comprising
oxycodone and naloxone in a substantially non-swellable diffusion
matrix, characterized in that the matrix is influenced with respect
to its substantial release characteristics by ethylcellulose and at
lease one fatty alcohol and that the preparation comprises
oxycodone and naloxone in a weight ratio of from about 25:1 to
about 1:1.
15. Preparation according to claim 14, characterized in that the
oxycodone and naloxone are present in the form of pharmaceutically
acceptable and equally active derivatives.
16. Preparation according to claim 15, characterized in that
oxycodone and naloxone are present as hydrochloride, sulfate,
bisulfate, tatrate, nitrate, citrate, bitatrate, phosphate, malate,
maleate, hydrobromide, hydroiodide, fumarate or succinate.
17. Preparation according to claim 16, characterized in that
oxycodone is present in excess referred to the unit dosage amount
of naloxone.
18. Preparation according to claim 17, characterized in that
oxycodone is present in an amount range of about 1 mg to about 50
mg.
19. Preparation according to claim 18, characterized in that
oxycodone is present in an amount range of about 10 mg to about 150
mg.
20. Preparation according to claim 19, characterized in that
preparation comprises a substantially non-swellable and non-erosive
diffusion matrix.
21. Preparation according to claim 20, characterized in that the
diffusion matrix comprises at least ethylcellulose and at least one
fatty alcohol as the components that essentially influence the
release behavior of the active compounds.
22. Preparation according to claim 21, characterized in that the
preparation does not comprise relevant parts of alkaline and/or
water-swellable substance.
23. Preparation according to claim 22, characterized in that the
fatty alcohols comprise lauryl, myrestyl, stearyl, cetostearyl,
ceryl and/or cetyl alcohol.
24. Preparation according to claim 23, characterized in that the
preparation comprises fillers and additional substances.
25. Preparation according to claim 24, characterized in that it
comprises magnesium stearate, calcium stearate and/or calcium
laureate and/or fatty acids.
26. Preparation according to claim 24, characterized in that it
comprises a flowing agent selected from the group consisting of
highly-disperse silica, talcum, corn starch, magnesium oxide,
magnesium stearate and calcium stearate.
27. Preparation according to claim 26, characterized in that
commercially available polymer mixtures which comprise
ethylcellulose are used instead of ethylcellulose.
28. Preparation according to claim 27, characterized in that the
preparation has been formulated for oral, nasal, rectal application
or for application by inhalation.
29. Preparation according to claim 28, characterized in that the
preparation is in the form of a tablet, pill, capsule, granule or
powder.
30. Preparation according to claim 29, characterized in that
preparation or precursors thereof are produced by build-up and/or
break-down granulation.
31. Preparation according to claim 29, characterized in that the
preparation or precursors thereof are produced by extrusion.
32. Preparation according to claim 31, characterized in that the
preparation can be stored over a period of at least 2 years under
standard conditions (60% relatively humidity, 25.degree. C.) in
accordance with admission guidelines.
33. A preparation according to claim 6, characterized in that
oxycodone is present in an amount range of from about 10 mg to
about 80 mg.
34. A preparation according to claim 7, characterized in that
oxycodone and naloxone are present in weight ratio ranges of from
about 5:1 to about 1:1.
35. A preparation according to claim 10, characterized in that the
preparation does not comprise relevant parts of derivatives of
acrylic acid and/or hydroxy alkyl celluloses.
36. A preparation according to claim 11, further comprising one or
more materials from the group consisting of lubricants, flowing
agents, plasticizers and the like.
37. A preparation according to claim 12, characterized in that it
comprises stearic acid.
38. A storage stable pharmaceutical preparation according to claim
14, comprising oxycodone and naloxone in a substantially
non-swellable diffusion matrix, characterized in that the matrix is
influenced with respect to its substantial release characteristics
by ethylcellulose and at lease one fatty alcohol and that the
preparation comprises oxycodone and naloxone in a weight ratio of
from about 5:1 to about 1:1.
39. A preparation according to claim 19, characterized in that
oxycodone is present in an amount range of about 10 mg to about 80
mg.
40. A preparation according to claim 22, characterized in that the
preparation does not comprise relevant parts of derivatives of
acrylic acid and/or hydroxy alkyl celluloses.
41. A preparation according to claim 24, further comprising one or
more materials from the group consisting of lubricants, flowing
agents, plasticizers and the like.
42. A preparation according to claim 25, characterized in that it
comprises stearic acid.
43. A preparation according to claim 27, characterized in that the
commercially available polymer mixture is Surelease.RTM.
E-7-7050.
44. A preparation according to claim 15, characterized in that the
pharmaceutically acceptable and equally active derivatives are the
free-base, salts and the like.
Description
[0001] The invention concerns a storage-stable pharmaceutical
preparation comprising oxycodone and naloxone.
[0002] The treatment of severe pain which results from diseases
such as cancer, rheumatism and arthritis is central to the
treatment of these diseases. The range of pain felt by tumor
patients comprises pain of the periosteum and of the bone itself,
as well as visceral pain and pain in soft tissues. All such pain
forms render the daily life of patients intolerable and often lead
to depressive states. Successful pain therapy resulting in a
lasting improvement of quality of life for the patients is
therefore equally important to the success of a comprehensive
therapy, as is the treatment of the actual causes of the
disease.
[0003] Regarding the importance of a successful pain therapy, the
World Health Organization (WHO) has developed a 4-step model for
the treatment of patients with tumor pain. This model has proven to
be effective in daily routine practice and can be extended to
patients suffering from chronic pain or pain forms which result
from diseases other than cancer. Depending on the intensity,
quality and localization of pain, four steps are distinguished
during this therapy, with each next step being indicated if the
effect of the pain relief agent used until then is no longer
sufficient (Ebell, H. J.; Bayer A. (Ed.): Die Schmerzbehandlung von
Tumorpatienten, Thieme 1994 (Supportive Mal.beta.nahmen in der
Onkologie, Band 3) and Zech, D.; Grond, S.; Lynch, J.; Hertel, D.;
Lehmann, K.: Validation of World Health Organisation Guidelines for
Cancer Pain Relief: a 10-year prospective study, Pain (1995), 63,
65-76). According to this 4-step model of the WHO, opioid
analgesics take a central role in treating pain. The group of
opioid analgesics comprises, besides morphine which represents the
prototype of these pharmaceutically active agents, also oxycodone,
hydromorphone, nicomorphine, dihydrocodeine, diamorphine,
papaveretum, codeine, ethylmorphine, phenylpiperidine and
derivatives thereof; methadone, dextropropoxyphene, buprenorphine,
pentazocine, tilidine, tramadol and hydrocodone. The
ATC-Classification (Anatomical Therapeutic Chemical Classification)
of the WHO indicates whether the pharmaceutically active agent
represents an opiod analgesic, or not. The pronounced
pain-relieving effect of opioid analgesics is due to the imitation
of the effect of endogenous, morphine-like acting substances
("endogenous opioids"), whose physiological function is to control
the reception and processing of pain stimuli.
[0004] Opioids repress the propagation of pain stimuli. Besides the
immediate inhibition of neuronal excitatory signal transduction in
the spinal cord caused by opioids, an activation of such nerve
tracts is relevant, which project form the brainstem into the
spinal cord. This activation results in an inhibition of pain
propagation in the spinal cord. Moreover, opioids limit the pain
reception of the thalamus and by affecting the limbic system they
influence the affective pain evaluation.
[0005] Opioid receptors are found at different sites in the body.
Receptors of the intestine and brain are of particular importance
for pain therapy by opioids, especially as their occupation results
in different side effects.
[0006] Opioid analgesics are considered to be strong agonists if
they bind with high affinity to opioid receptors and induce a
strong inhibition of pain reception. Substances that also bind with
high affinty to opioid receptors, but that do not provoke a
reduction of pain reception and which thereby counteract the opioid
agonists, are designated as antagonists. Depending on the binding
behaviour and the induced activity, opioids can be classified as
pure agonists, mixed agonists/antagonists and pure antagonists.
Pure antagonists comprise, for example, naltrexone, naloxone,
nalmefene, nalorphine, nalbuphine, naloxoneazinen,
methylnaltrexone, ketylcyclazocine, norbinaltorphimine, naltrindol,
6-13-naloxol und 6-13-naltrexol (Forth W.; Henschler, D.; Rummel
W.; Starke, K.: Allgemeine und Spezielle Pharmakologie und
Toxikologie, 7. Auflage, 1996, Spektrum Akademischer Verlag,
Heidelberg Berlin Oxford).
[0007] Due to their good analgesic efficiency compounds such as
oxycodone, tilidine, buprenorphine und pentazocine, have been used
in the form of medicaments for pain therapy. Medicaments such as
Oxigesic.RTM. (wherein oxycodone is the analgesic active compound)
und Valoron.RTM. (wherein tilidine is the analgesic active compound
) have proven valuable for pain therapy.
[0008] However, use of opioid analgesics for pain therapy might go
along with undesirable side effects. Thus, long-term use of opioid
analgesics can lead to psychological and physical dependence.
[0009] Especially the physical dependence of patients suffering
from pain to opioid analgesics leads to the development of
tolerance, meaning that upon extended intake, increasingly higher
doses of the pain relieving agent have to be taken by the patient,
in order to experience pain relief. The euphoregenic effect of
opioid analgesics often leads to the abuse of pain relievers. Drug
abuse and psychological dependence are a common phenomenon,
especially among teenagers. These dangerous effects are especially
caused by the substances with strong analgesic capacity, and can
range from undesired habituation to fully developed addiction.
However, these substances are legitimately used for medical
purposes and medicine cannot do without them.
[0010] Besides the mentioned disadvantages, the use of potent
opioid analgesics for pain therapy often also lead to undesirable
side effects, such as obstipation, breath depression, sickness and
sedation. Less frequently, the urge or the disability to pass water
are observed. Different attempts have been made to counteract the
habituation processes and the other side effects occurring during
pain therapy. This can be done, e.g. by traditional treatment
methods. In the case of drug addiction this might be a drug
withdrawal treatment, and in the case of obstipation, this might be
done by administration of laxatives.
[0011] Other attempts aim at minimizing the addictive and
habituation forming potential of opioid analgesics, as well as
their other side effects by the administration of antagonists which
counteract the opioid analgesic. Such antagonists might be
naltrexone or naloxone.
[0012] There have been numerous proposals and suggestions, how the
application of the aforementioned active compounds could be used to
avoid undesired habituation and dependence, or even addiction.
[0013] U.S. Pat. Nos. 3,773,955 und 3,966,940 suggested to
formulate analgesics in combination with naloxone, in order to
prevent dependence-promoting effects such as euphoria and the like,
upon parenteral application. The avoidance of side effects such as
obstipation has not been addressed.
[0014] To limit the parenteral abuse of oral application forms,
U.S. Pat. No. 4,457,933 suggested the combination of morphine with
naloxone in defined ranges. The avoidance of side effects such as
obstipation has also not been mentioned.
[0015] U.S. Pat. No. 4,582,835 describes, again in order to avoid
abuse, a preparation comprising a combination of buprenorphine and
naloxone, that is to be administered either parenterally or
sublingually.
[0016] European application EP 0 352 361 A1 concerns the treatment
of obstipation during pain therapy by the oral application of an
opioid analgesic and one antagonist, with the antagonist being a
pro-drug form of either naltrexone or naloxone. Avoidance of abuse
of the opioid analgesic is not an issue in this application.
[0017] German patent application DE 43 25 465 A1 also concerns the
treatment of obstipation during pain therapy using a preparation
which comprises an opioid analgesic and an antagonist. The
characterizing feature of this disclosure is that the antagonist
which can be naloxone, has to be present in higher amounts than the
opioid analgesic which is preferably morphine. This is to ensure
that the antagonist unfolds its anti-obstipation effect without
reducing the analgesic activity of the agonist. The avoidance of
abuse of the opioid analgesic is not an issue in this
application.
[0018] In order to avoid side effects such as obstipation and
breath depression during pain therapy, preparations have been
introduced on the market which can be taken orally and comprise an
opioid analgesic and the opioid antagonist, naloxone. The
medicament Talwin.RTM. of Windrop/Sterling comprises pentazocine
and naloxone. The medicament Valoron.RTM. of Godeke comprises a
tilidine-naloxone combination.
[0019] Besides the potent analgesic effect, the reduction of
addictive potential and the avoidance of side effects, medicaments
usable for a successful pain therapy should provide for additional
characteristics.
[0020] Generally, medicaments have to be formulated in a way that
the active compounds are stable as long as possible, under standard
storage conditions. Medicaments have also to be formulated in a way
that the intended release profiles of the active compounds do not
change upon long-term storage.
[0021] Additionally, (also in the case of
agonist/antagonist-combinations) the release profile of each single
active compound should be selectable as required. The measures
applied in order to achieve this should not hamper or even prevent
that the release profiles of additional active compounds (e.g. in
the case of combinations of different active compounds) can be
chosen as required. Consequently, there should be no mutual
dependency of the release profiles.
[0022] Medicaments suitable for pain therapy should either contain
the active compounds in such amounts or be formulated in such ways
that they have to be taken by the patients only rarely. The easier
the application scheme for a pain reliever is, and the more evident
it is for the patient why and how often he should take which
tablet, the more exactly he will adhere to the physician's orders.
The necessity to take the pain reliever only infrequently, will
result in a high willingness of the patient to take the pain
reliever (compliance).
[0023] Through the use of so called sustained-release formulations,
i.e. formulations of medicaments from which the active compounds
are released over an extended period of time, it has been tried to
lower the frequency by which pain relieving medicaments have to be
taken, and thereby to increase the compliance of patients. Such
sustained-release formulations also make sense in that the
sustained release of an opioid analgesic reduces the addictive
potential of this active compound.
[0024] This is due to the fact that the addictive potential of an
active compound is not defined by the compound itself, but rather
by the way it is administered and the pharmaco-dynamics resulting
therefrom. Besides the psychotropic effect of an opioid, the rate
by which the brain encounters an opioid, is more decisive criterion
for the risk of dependency than the active compound itself (Nolte,
T.: STK-Zeitschrift fur angewandte Schmerztherapie, 2001, Vol.
2).
[0025] The medicament Oxigesic.RTM. of Purdue is a preparation from
which the opioid analgesic oxycodone is released in a sustained
manner. Due to this formulation, the frequency by which the
medicament has to be taken as well as the addictive potential is
lowered, however the side effects remain and the danger of
developing addiction cannot be excluded, as Oxigesic.RTM. does not
contain opioid-antagonists.
[0026] According to the already mentioned European patent
application EP 0 352 361 A, neither the opioid analgesic nor the
antagonist are formulated to be released in a sustained manner.
Accordingly, the time period during which such preparations are
effective is limited and preparations have to be taken multiple
times per day. The desired compliance of the patient is not
achieved. This application also does not disclose the advantages of
formulations of preparations that are characterized by a
time-stable and independent release of the active compounds. The
storage stability of such preparations is also not addressed by
this disclosure.
[0027] German patent application DE 43 25 465 A1 discloses
formulations according to which obstipation occurring during pain
therapy is prevented by the sustained release of the opioid agonist
while the antagonist, which is present in excess must not be
released in a sustained manner. Due to the high First-Pass-Effect
of naloxone, comparably large amounts of this compound have
therefore to be used. This application discloses neither the
advantages nor the formulations of preparations, which are
characterized by time-stable and independent release of the active
compounds. The storage stability of such preparations is also not
an issue of this disclosure. A doctor using preparations according
to this disclosure has therefore to carry out extensive titration
experiments each time he wants to increase the dosage.
[0028] The company Godeke offers, under the trademark Valoron.RTM.,
a pain reliever that comprises a tilidine-naloxone-combination.
According to the product literature, a formulation is used from
which both active compounds are released in a sustained manner. The
matrix used comprises a relevant part of water-swellable material
(HPMC) and has therefore to be considered as a swellable (and
possibly partially erosive) diffusion matrix. A disadvantage of
this known formulation is that tilidine and naloxone, given
identical mass ratios but different absolute amounts, show
different release profiles. The release rates of the agonist and
the antagonist are not independent from each other, which is
probably due to the sustained release formulation used.
Accordingly, it is necessary for the physician to carry out
extensive titration experiments for each individual patient if he
wants to increase the dosage even though he does not change the
mass ratio of tilidine:naloxone, as he cannot assume that the
release profiles of both components will remain constant. The range
of therapeutically usable amounts of the analgesic that are
available to the doctor is therefore limited.
[0029] It is one of the objectives of the present invention to
provide a pharmaceutical preparation for pain therapy that, given a
high analgesic activity, is characterized by a reduced abuse
potential and reduced side effects, said preparation also being
characterized by a reduced administration frequency and therefore
providing increased compliance, as well as the ability for
individual adaptation of the dosage for each patient. A further
objective of the present invention is to provide formulations for
pharmaceutical preparations usable in pain therapy that make sure
that the active compounds of said pharmaceutical preparations are
stable over a long storage time, and that the release of the active
compounds remain reproducibly invariant and independent from each
other even after long-term storage.
[0030] The feature combination of the independent claim serves to
attain these, and further objectives which can be noted from the
ensuing description of the invention. Preferred embodiments of the
invention are defined in the subclaims.
[0031] According to the invention, the objectives are attained by
providing a storage-stable pharmaceutical preparation comprising
oxycodone and naloxone wherein said preparation is formulated such
that the active compounds are released in a sustained, invariant
and independent manner.
[0032] By the combination of oxycodone (in an analgesically
effective amount) and naloxone it is ensured that preparations
according to the invention show an efficient analgesic activity and
that at the same time, common side effects such as obstipation,
breath depression and development of addiction are suppressed, or
at least significantly reduced. The matrix formulation, which is
stable over extended periods of time, ensures permanently that
agonist as well as antagonist are always released in predetermined
percentages and that their release rates do not influence each
other. Thereby, abuse of the medicament, which requires that the
oxycodone can selectively be extracted from the formulation, is
prevented. The formulation according to the invention disables
selective extraction of the agonist from the preparation without
the corresponding amount of the antagonist, independent of the
absolute and relative amounts of agonist and antagonist chosen.
[0033] Moreover, the formulation of a medicament according to the
invention ensures that, given identical relative amounts, the
active compounds show equal release profiles, independent of the
absolute amount present. Such an independent release behaviour
provides a wide range of useable absolute amounts of the analgesic
active substance to the physician, given that the optimal
agonist/antagonist ratio is known. Thus, it is possible to
comfortably adjust the dosage for each individual patient, either
by a step-wise dosage increase or, if necessary, a step-wise dosage
reduction. This ability to adjust the dosage for the individual
patient is extremely useful from a medical point of view.
[0034] The characterizing features of the present invention, which
comprise the sustained, invariant and independent release of the
active compounds ensure additionally that pharmaceutical
preparations produced according to the invention are characterized
by a low administration frequency, so that high patient compliance
is achieved. Furthermore, preparations according to the invention
allow the doctor to adjust the dosage for individual patients.
Preparations according to the invention enable use over a broad
range with respect to the useable absolute amounts of the active
compounds and ensure that the active compounds, even after
long-term storage, become effective with equal release
profiles.
[0035] According to the present invention, sustained release of
active compounds means that pharmaceutically active substances are
released from a medicament over a longer period of time than they
are from known formulations for immediate release. Preferably, the
release takes place over a time period of two to twenty four hours,
of two to twenty hours, especially preferred over a time period of
two to sixteen hours or two to twelve hours, with the
specifications satisfying the legal and regulating
requirements.
[0036] According to the invention, formulations of medicaments that
ensure such a sustained release of the active compounds from the
preparation, are designated as retard formulations, as sustained
release formulations or as prolonged release formulations. In the
context of the instant invention, "sustained release" does not mean
that the active compounds are released from the formulation or the
medicament in a pH-dependent manner. According to the invention,
the release of the active compounds rather occurs in a
pH-independent manner. According to the invention, the term
"sustained release" refers to the release of active compounds from
a medicament over an extended period of time. It does not imply the
controlled release at a defined place; therefore, it does not mean
that the active compounds are either released only in the stomach,
or only in the intestine. (Of course, such a release at a defined
place could individually be achieved by, e.g., enteric coating of
the medicament. However, this presently seems not to be
advantageous.)
[0037] According to the invention, "independent release" means
that, given the presence of at least two active compounds, a change
of the absolute amount of one compound does not influence the
release profiles of the other compounds so that the release
profiles of the other compounds are not changed. For formulations
according to the invention such an independent release behaviour is
independent of the pH value, for which the release is measured, or
of the production process. The pH independency particularly applies
to the acidic range, i.e. for pH values<7. The release profile
(or release behaviour) is defined as the change of the release of
the active compound from the formulation with time, with the amount
of each active compound released provided in percents of the total
amount of the active compound. The release profile is determined by
known tests.
[0038] Specifically, this means that for example the release
profile of oxycodone, as it is observed for an
oxycodone/naloxone-combination with 12 milligrams oxycodone and 4
milligrams naloxone, does not change, if a corresponding
preparation with the same formulation contains 12 milligrams
oxycodone, but 6 milligrams naloxone.
[0039] The independent release feature preferably refers to the
situation where preparations of substantially equal composition are
compared for the release profile. Preparations of substantially
equal composition have different amounts of the active compounds
but are otherwise basically the same with respect the components of
the composition which essentially influence the release
behaviour.
[0040] If e.g. the above-mentioned preparations are compared (with
the first preparation comprising 12 mg oxycodone and 4 mg naloxone
and the second preparation comprising 12 mg oxycodone and 6 mg
naloxone) both preparations, provided that they have the same total
weight, will provide for the same release profile for oxycodone and
naloxone if the difference in the naloxone amount is replaced by a
component in the formulation that typically does not influence the
release behaviour. As shown in the Example section, the difference
in the amount of naloxone my be replaced by a typical
pharmaceutically inert filler such as lactose without changing the
release profiles.
[0041] The person skilled in the art is well aware that if the
amount of the active compound in which two preparations differ is
replaced by a substance that is essential for the release behaviour
of the formulation, such as ethylcellulose or a fatty alcohol,
differences in the release behaviour may occur. Thus, the
independent release feature preferably applies to formulations that
have different amounts of the active compounds but are otherwise
identical or at least highly similar with respect to the components
that essentially influence the release behaviour (given that
formulations of the same total weight are compared).
[0042] According to the invention, "invariant release behaviour" or
"invariant release profile" is defined so that the percentage of
the absolute amount of each active compound released per time unit
does not significantly change and remains sufficiently constant
(and thus does not substantially change) if absolute amounts are
changed. Sufficiently constant percentages mean that the percentage
released per time unit deviates from a mean value by not more than
20%, preferably by not more than 15% and especially preferably by
not more than 10%. The mean value is calculated from six
measurements of the release profile. Of course, the amount released
per time unit has to satisfy the legal and regulatory
requirements.
[0043] Specifically, this means for example that given an
oxycodone/naloxone combination of 12 mg oxycodone and 4 mg
naloxone, during the first 4 hours 25% oxycodone and 20% naloxone
are released. If the oxycodone/naloxone combination instead
contains 24 mg oxycodone and 8 mg naloxone, during the first 4
hours also 25% oxycodone and 20% naloxone will be released. In both
cases the deviation will not be more than 20% from the mean value
(which in this case is 25% oxycodone and 20% naloxone).
[0044] As outlined for the independent release behaviour, the
invariant release feature also preferably refers to a situation
where preparations of substantially equal composition are compared.
Such preparation differ with respect to the amount of the active
compounds, but are of the same or at least highly similar
composition with respect to the release-influencing components of
the preparation. Typically, the difference in the amount of an
active compound will be replaced by the amount of a pharmaceutical
inert excipient which does not substantially influence the release
behaviour of the preparation. Such a pharmaceutical excipient may
be lactose, which is a typical filler in pharmaceutical
preparations. The person skilled in the art is well aware that the
invariant release feature may not apply to preparations where the
difference in the amount of an active compound is replaced by
substances that are known to essentially influence the release
behaviour of the preparation, such as ethylcellulose or fatty
alcohols.
[0045] In the Example section it is set out that if one preparation
comprises 20 mg oxycodone and 1 mg naloxone or 20 mg oxycodone and
10 mg naloxone, with the difference in naloxone being replaced by
lactose, that the two preparations of identical weight provide for
the same release profiles, so that they exhibit a sustained,
invariant and independent release behaviour.
[0046] According to the invention "storage stable" or "storage
stability" means that upon storage under standard conditions (at
least two years at room temperature and usual humidity) the amounts
of the active compounds of a medicament formulation do not deviate
from the initial amounts by more than the values given in the
specification or the guidelines of the common Pharmacopoeias.
According to the invention, storage stability also means that a
preparation produced according to the invention can be stored under
standard conditions (60% relative humidity, 25.degree. C.) as it is
required for admission to the market.
[0047] According to the invention, "storage stable" or "time
stable" also means that after storage under standard conditions the
active compounds show release profiles as they would upon immediate
use without storage. According to the invention, the admissible
fluctuations with respect to the release profile are characterized
in that the amount released per time unit fluctuates by no more
than 20%, preferably no more than 15% and especially preferably no
more than 10%, with respect to a mean value. The mean value is
calculated from six measurements of the release profile.
[0048] Preferably, the release of the active compounds from a
sustained release formulation is determined by the Basket Method
according to USP at pH 1.2 or pH 6.5 with HPLC. Storage stability
is preferably determined by the Basket Method according to USP at
pH 1.2 with HPLC.
[0049] According to the invention, a "non-swellable" or
"substantially non-swellable" diffusion matrix is a matrix
formulation for which the release of the active compounds is not
influenced (or at least not to a relevant degree) by swelling of
the matrix (particularly in the physiological fluids of the
relevant target sites in the patient's body).
[0050] According to the invention, the term "substantially
non-swellable" diffusion matrix also refers to a matrix whose
volume will increase by approximately 300%, preferably by
approximately 200%, more preferably by approximately 100%, by
approximately 75% or by approximately 50%, even more preferably by
approximately 30% or by approximately 20% and most preferably by
approximately 15%, by approximately 10%, by approximately 5% or by
approximately 1% in aqueous solutions (and particularly in the
physiological fluids of the relevant target sites in the patient's
body).
[0051] In the context of the present invention, "agonist" or
"analgesic" always refers to oxycodone. In the context of the
present invention "antagonist" always refers to naloxone.
[0052] Preparations produced according to the invention can be
applied orally, nasally, rectally and/or by inhalation for use in
pain therapy. According to the invention, parenteral application is
not envisaged. Especially preferred is a formulation for oral
application.
[0053] Even though this might not be expressly stated, the term
"agonist" or "antagonist" always comprises pharmaceutical
acceptable and equally acting derivatives, salts and the like. If,
for example, oxycodone or naloxone is mentioned, this also
comprises, besides the free base, their hydrochloride, sulfate,
bisulfate, tatrate, nitrate, citrate, bitratrate, phosphate,
malate, maleate, hydrobromide, hydrojodide, fumarate, succinate and
the like.
[0054] According to the invention, agonists and antagonists are
formulated in a way that they are released from the resulting
pharmaceutical preparation in a sustained, independent and
invariant manner. This does not mean that the antagonist is in
excess compared to the agonist. On the contrary, it is preferred
that in formulations comprising an agonist/antagonist combination,
that show a release profile in accordance with the invention, the
agonist is in excess compared to the antagonist.
[0055] The excess of the agonist is defined based on the amount of
the unit dosage of the antagonist present in the combination
preparation. The extent of the excess of the opioid agonist is
usually given in terms of the weight ratio of agonist to
antagonist.
[0056] 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, especially preferred are the weight ratio ranges
15:1, 10:1, 5:1, 4:1, 3:1, 2:1 and 1:1.
[0057] The absolute amounts of agonist and antagonist to be used
depend on the choice of the active compounds. According to the
invention, care has to be taken that agonist and antagonist are
released from the pharmaceutical preparation that has been
formulated for sustained release, only in an independent and
invariant manner.
[0058] 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.
[0059] 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.
[0060] According to the invention, the ratio between oxycodone and
naloxone has to be chosen in such a way that release profiles for
both active substances in accordance with the invention are
guaranteed and that the agonist can display its analgesic 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 analgesic 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
analgesically effective opioid agonists.
[0061] According to the invention, generally common formulations
can be used, given that these formulations ensure that the active
compounds are released from the preparation in a sustained,
independent and invariant manner. According to the invention, those
formulations have to be chosen such that the active compounds are
storage stable.
[0062] Matrix-based retardation formulations may preferably be used
as formulations that provide a release of agonist and antagonist in
accordance with the invention. According to the invention,
especially preferred are formulations based on a substantially
non-swellable diffusion matrix. At the moment, formulations with an
erosive matrix or a swellable diffusion matrix are not
preferred.
[0063] According to the invention, the matrix that provides the
sustained release of the active compounds, has to be chosen in such
a way that the release of the active compounds occurs in a
sustained, independent and invariant manner. Preferably such
matrices comprise polymers based on ethylcellulose, with
ethylcellulose being an especially preferred polymer. Specifically
preferred are matrices comprising polymers as they are available on
the market under the trademark Surelease.RTM.. Particularly
preferred is the use of Surelease.RTM.E-7-7050
[0064] Formulations with a release behaviour according to the
invention comprise particularly matrices that comprise
ethylcellulose and at least one fatty alcohol as the components
that essentially influence the release characteristics of the
matrix. The amounts of ethylcellulose and the at least one fatty
alcohol may significantly vary so that preparations with different
release profiles may be achieved. Even though the inventive
preparations usually will comprise both of the afore-mentioned
components, in some cases it may be preferred that the preparations
comprise only ethylcellulose or the fatty alcohol(s) as the release
determining components.
[0065] Matrices based on polymethacrylate (as, e.g.
Eudragit.RTM.RS30D and Eudragit.RTM.RL30D) or matrices which
comprise relevant amounts of water-swellable material, especially
of hydroxyalkyl cellulose derivates such as HPMC, are presently
preferably avoided according to the invention.
[0066] Matrices that are in accordance with the invention can be
used to produce preparations that release active compounds in a
sustained, independent and invariant manner and that release equal
amounts of the active compounds per time unit. Specifically, this
means that in the case of a oxycodone/naloxone combination
containing 12 mg oxycodone und 4 mg naloxone, 25% oxycodone and 25%
naloxone are released within the first 4 hours. Correspondingly, in
the case of a oxycodone/naloxone combination containing 24 mg
oxycodone and 8 mg naloxone, 25% oxycodone and 25% naloxone are
released during the first 4 hours, with the deviation in both cases
being no more than 20% of the mean value (which in this case is 25%
oxycodone or naloxone).
[0067] Such an equal release behaviour for both active compounds
may be desirable for medical aspects.
[0068] A preferred embodiment of the invention relates to
preparations that release 1% to 40%, preferably 5% to 35%, more
preferably between 10% and 30% and even more preferably between 15%
and 25% of oxycodone and/or naloxone after 15 minutes. In other
preferred embodiments of the invention, 15% to 20%, 20% to 25%,
approximately 15%, approximately 20% or approximately 25% of
oxycodone and/or naloxone are released after 15 minutes.
[0069] Another preferred embodiment of the invention relates to
preparations that release between 25% to 65%, preferably between
30% to 60%, more preferably between 35% to 55% and even more
preferably between 40% to 50% of oxycodone and/or naloxone after
one hour. Preferred embodiments of the invention also relate to
preparations that release between 40% to 45%, 45% to 50%,
approximately 40%, approximately 45% or approximately 50% of
oxycodone and/or naloxone after one hour.
[0070] Yet another preferred embodiment of the invention relates to
preparations that release between 40% to 80%, preferably between
45% to 75%, more preferably between 45% to 70% and even more
preferably between 45% to 50%, 50% to 55%, 55% to 60%, 60% to 65%
or 65% to 70% of oxycodone and/or naloxone after 2 hours. Preferred
embodiments also comprise preparations that release approximately
45%, approximately 50%, approximately 55%, approximately 60%,
approximately65% or approximately 70% of oxycodone and/or naloxone
after 2 hours.
[0071] One preferred embodiment of the invention relates to
preparations that release 70% to 100%, preferably between 75% to
95%, more preferably between 80% to 95%, and even more preferably
between 80% and 90% of oxycodone and/or naloxone after 4 hours.
Preferred embodiments of the invention also relate to preparations
that release between 80% to 85%, 85% to 90%, approximately 80%,
approximately 85% or approximately 90% of oxcodone and/or naloxone
after 4 hours. One preferred embodiment of the invention also
relates to preparations that release between 70% to 100%,
preferably between 75% to 100%, more preferably between 80% to 95%
and even more preferably between 80% to 85%, between 85% to 90% or
between 90% to 95% of oxycodone and/or naloxone after 7 hours.
Preferred embodiments of the invention also relate to preparations
that release approximately 80%, approximately 85%, approximately
90% or approximately 95% of oxycodone and/or naloxone after 7
hours.
[0072] Yet another preferred embodiment of the invention relates to
preparations that release between 85% to 100%, preferably between
90% to 100%, more preferably between 95% to 100% and even more
preferably approximately 95% or 100% of oxycodone and/or naloxone
after 12 hours.
[0073] According to the invention, formulations that provide a
release of the active compounds in accordance with the invention
may comprise, besides the matrix forming polymers, fillers and
additional substances, such as granulating aids, lubricants, dyes,
flowing agents and plasticizers.
[0074] Lactose, glucose or saccharose, starches and their
hydrolysates, microcrystalline cellulose, cellatose, sugar alcohols
such as sorbitol or mannitol, polysoluble calcium salts like
calciumhydrogenphosphate, dicalcium- or tricalciumphosphat may be
used as fillers.
[0075] Povidone may be used as granulating aid.
[0076] Highly-disperse silica (Aerosil.RTM.), talcum, corn starch,
magnesium oxide and magnesium- or calcium stearate may preferably
be used as flowing agents or lubricants.
[0077] Magnesium stearate and/or calcium stearate can preferably be
used as lubricants. Fatty acids like stearic acid, or fats like
hydrated castor oil can also preferably be used.
[0078] Polyethylene glycols and fatty alcohols like cetyl and/or
stearyl alcohol and/or cetostearyl alcohol can also be used as
additional substances that influence retardation.
[0079] If fillers and additional substances such as dyes and the
mentioned lubricants, flowing agents and plasticizers are used,
care has to be taken that according to the invention only such
combinations together with the matrix forming substance and/or the
matrix forming substances are used, which ensure release profiles
of the active compounds in accordance with the invention.
[0080] All these additional components of the formulations will be
chosen in such a way that the release matrix receives the character
of a substantially non-water- or non-buffer-swellable and
non-erosive diffusion matrix.
[0081] According to the invention, 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.
[0082] Preparations in accordance with the invention 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 in accordance with the
invention. 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 in
accordance with the invention.
[0083] 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.
[0084] Pharmaceutical preparations or preliminary stages thereof
which are in accordance with the invention can be produced by
build-up or break-down granulation. A preferred embodiment is the
production by spray granulation with subsequent drying of the
granules. Another preferred embodiment is the production of
granules by build-up granulation in a drum or on a granulating
disk. The granules may then be pressed into e.g. tablets using
appropriate additional substances and procedures.
[0085] The person skilled in the art is familiar with granulating
technology as applied to pharmaceutical technology. The embodiment
examples (see below) disclose specific embodiments of the
invention. However, it is well within the scope of the person
skilled in the art to adapt the parameters of the process in order
to achieve specific purposes.
[0086] Production of pharmaceutical preparations or preliminary
stages thereof, which are in accordance with the invention, by
extrusion technology is especially advantageous. In one preferred
embodiment, pharmaceutical preparations or preliminary stages
thereof are produced by melt extrusion with co- or counter-rotating
extruders comprising two screws. Another preferred embodiment is
the production by means of extrusion, with extruders comprising one
or more screws. These extruders may also comprise kneading
elements.
[0087] Extrusion is also a well-established production process in
pharmaceutical technology and is well known to the person skilled
in the art. The person skilled in the art is well aware that during
the extrusion process, various parameters, such as the feeding
rate, the screw speed, the heating temperature of the different
extruder zones (if available), the water content, etc. may be
varied in order to produce products of the desired characteristics.
The Example section provides for numerous examples of preparations
according to the invention that have been produced by
extrusion.
[0088] The aforementioned parameters will depend on the specific
type of extruder used. During extrusion the temperature of the
heating zones, in which the components of the inventive formulation
melt, may be between 40 to 120.degree. C., preferably between 50 to
100.degree. C., more preferably between 50 to 90.degree. C., even
more preferably between 50 to 70.degree. C. and most preferably
between 50 to 65.degree. C., particularly if counter-rotating twin
screw extruders (such as a Leistritz Micro 18 GGL) are used. The
person skilled in the art is well aware that not every heating zone
has to be heated. Particularly behind the feeder where the
components are mixed, cooling at around 25.degree. C. may be
necessary. The screw speed may vary between 100 to 500 revolutions
per minute (rpm), preferably between 100 to 250 rpm, more
preferably between 100 to 200 rpm and most preferably around 150
rpm, particularly if counter-rotating twin screw extruders (such as
a Leistritz Micro 18 GGL) are used. The geometry and the diameter
of the nozzle may be selected as required. The diameter of the
nozzle of commonly used extruders typically is between 1 to 10 mm,
preferably between 2 to 8 mm and most preferably between 3 to 5 mm.
The ratio of length versus diameter of the screw of extruders that
may be used for production of inventive preparations is typically
around 40:1.
[0089] Generally, the temperatures of the heating zones have to be
selected such that no temperatures develop that may destroy the
pharmaceutically active compounds. The feeding rate und screw speed
will be selected such that the pharmaceutically active compounds
are released from the preparations produced by extrusion in a
sustained, independent and invariant manner and are storage stable
in the matrix. If e.g. the feeding rate is increased, the screw
speed may have to be increased correspondingly to ensure the same
retardation.
[0090] The person skilled in the art knows that all the
aforementioned parameters depend on the specific production
conditions (extruder type, screw geometry, number of components
etc.) and may have to be adapted such that the preparations
produced by extrusion provide for a sustained, independent and
invariant release as well as for the afore-mentioned storage
stability.
[0091] The person skilled in the art can infer from the Examples
(see below) that by changing the parameters during extrusion and by
changing the composition with respect to the compounds that are
substantially responsible for the release behaviour of the
preparations, preparations with different release profiles may be
obtained. Thus, the present invention allows to first produce a
preparation with a desired release profile for oxycodone and
naloxone by e.g. varying the amount of fatty alcohols or the
matrix-forming polymer ethylcellulose as well as production
parameters such as temperature, screw speed (during extrusion) or
pressure power during tablet production.
[0092] Once a preparation with the desired release profile has been
obtained, the inventive preparations according to the invention
allow the person skilled in the art to change the amounts of the
preparations with respect to the active compounds as outlined
above. Preparations comprising different amounts of the active
compounds but of otherwise substantially equal composition,
however, will then provide for the features of sustained, invariant
and independent release.
[0093] The Example section therefore discloses numerous examples
showing that preparations with different release profiles may be
obtained by changing the amount of e.g. ethylcellulose. Other
examples show that once a preparation has been established with
desired release profiles, the change in the amount of naloxone will
not influence the release behaviour of such preparations if the
difference in the amount of the active compound is replaced by
pharmaceutically inert excipients such as lactose.
[0094] Examples that display highly advantageous embodiments of the
invention are set out below. Additionally examples are given that
emphasize the advantages of preparations according to the invention
compared to common formulations. The examples are not to be
interpreted as limiting the possible embodiments of the
invention.
EXAMPLE 1
Production of Tablets with Different Oxycodone/Naloxone Amounts in
a Non-Swellable Diffusion Matrix by Spray Granulation
[0095] The following amounts of the listed components were used for
the production of oxycodone/naloxone tablets according to the
invention.
1 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
[0096] The Surelease.RTM. E-7-7050 polymer mixture used had the
following composition.
2 Surelease .RTM. Ethylcellulose 20 cps Dibutylsebacate
Ammoniumhydroxide Oleic acid Siliciumdioxide Water
[0097] 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
[0098] The following amounts of the listed components were used for
the production of the oxycodone/naloxone tablets according to the
invention.
3 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
[0099] The listed amounts of oxycodone HCl, naloxone HCl,
ethylcellulose 45 cpi, 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. The extruder has a screw geometry, as shown in FIG.
1.
[0100] 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
[0101] 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.
[0102] One recognizes from FIG. 2 and the values listed in 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 done amounts.
4 Ox/Nal- Time OxNal-0 5-O Ox/Nal-5-N Ox/Nal-10-O Ox/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
[0103] 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%. 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
[0104] 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.
[0105] The following release rates were measured for 12 hours at pH
1.2:
5 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
[0106] The following release rates were measured for 1 hour at pH
1.2 and 11 hours at pH 6.5:
6 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
[0107] 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.
[0108] The comparison of the values given in the Tables of Example
4 and the Table of Example 3 make clear that independent of the
production process, active compounds are released in equal amounts
from the preparations. For example, 89.4% of oxycodone is released
from spray-granulated tablets (Ox/Nal-10-tablets, see Example 3) at
420 minutes, while 92.9% is released from extruded tablets
(Oxy/Nal-Extr-1.2-O, Example 4) at 420 minutes. The release of
oxycodone from extruded tablets thus deviates by 1.1% from the mean
value of the release of oxycodone from spray-granulated tablets
(91.9% at 420 minutes). 93.5% of naloxone is released from
spray-granulated tablets (Ox/Nal-10-tablets, see Example 3) at 420
minutes, while 93.9% is released from extruded tablets
(Oxy/Nal-Extr.-1.2-O, Example 4) at 420 minutes. The release of
naloxone from extruded tablets thus deviates by 1.3% from the mean
value of the release of naloxone from spray-granulated tablets
(92.7% at 420 minutes).
[0109] Moreover, one can infer from a comparison of the values of
the Tables of Example 4 and from FIGS. 3a and 3b that independent
of the pH value at which the release rates have been measured the
release of oxycodone and naloxone remain equal and invariant.
EXAMPLE 5
Comparative Example: Release Behaviour of Valoron.RTM. Tablets
[0110] The release of the active substances from tablets was
monitored over a time period of 7 hours. Valoron.RTM. tablets with
50 mg tilidine and 4 mg naloxone (Ti/Nal-50/4) or 100 mg tilidine
and 8 mg naloxone (Ti/Nal-100/8) or 150 mg tilidine and 12 mg
naloxone (Ti/Nal-150/12) were tested by the Basket Method according
to USP for 1h at pH 1.2 and then for additional 6 h at pH 6.5 using
HPLC.
[0111] One recognizes from FIGS. 4A and 4B and the values listed in
the Table that in case of a swellable (and possibly erosive)
diffusion matrix with relevant amounts of HPMC, the release of
different amounts of tilidine varies significantly and is not
invariant for different amounts of naloxone. This applies in turn
to naloxone. This means that for this pH the release of the active
compounds is not independent of each other.
7 Ti/Nal- Ti/Nal- Ti/Nal- Ti/Nal- Ti/Nal- Ti/Nal- Time 50/4-T
50/4-N 100/8-T 100/8-N 150/12-T 150/12-N (min) Til Nal Til Nal Til
Nal 0 0 0 0 0 0 0 60 37.2 27.6 33.9 27.3 29.9 23.3 120 47.6 31.7
46.5 33.4 41.5 28.5 180 54.7 37.4 55 41.2 48.2 35 240 59.7 44 68.2
59.5 54.5 40.1 300 65.2 50.6 82.6 72.9 60.5 47.5 360 70.3 58 85.7
82.7 67.2 56.4 420 74.2 60.8 93.1 90.9 84.9 78.9
[0112] The release values refer to tilidine or naloxone (line 2)
and are given as percentages. The mean value for the release of
naloxone at e.g. 420 min is 78,87%. The maximal deviation at 420
min is 20,4%. Til und Nal stand for tilidine and naloxone and
indicate the active compound tested.
EXAMPLE 6
Structure Comparison of Tablets of Examples 1 and 2 with
Valoron.RTM. N Tablets by Electron Microscopy
[0113] For electron microscopy tablets were used that comprised 20
mg oxycodone and 10 mg naloxone and were produced either by spray
granulation according to Example 1 (Ox/Nal-10) or by extrusion
according to Example 2 (Oxy/Nal-Extr). Additionally, a Valoron.RTM.
N tablet with 100 mg Tilidin and 8 mg Naloxone was used. FIGS. 5A
and 5B show different magnifications of scanning electron
microscopy pictures of a Ox/Nal-10-tablet with a formulation
according to the invention which was produced by spray granulation.
FIGS. 6A and 6B show different magnifications of scanning electron
microscopy pictures of a Oxy/Nal-Extr-tablets with a formulation
according to the invention, which was produced by extrusion. FIGS.
7A and 7B show scanning electron microscopy pictures of the
Valoron.RTM. N-tablet.
[0114] From a comparison of the figures one can clearly see that
tablets with a formulation according to the invention have a
surface which is substantially finer and more homogeneously
structured and which shows fewer cracks than the Valoron.RTM.
tablet, regardless of whether the tablets have been produced by
spray granulation or extrusion. The structural difference is
possibly the reason for the different release behaviours of the
different preparations.
EXAMPLE 7
Production of Tablets with Different Oxycodone/Naloxone Amounts in
a Non-Swellable Diffusion Matrix by Extrusion
[0115] The following amounts of the listed components were used for
the production of oxycodone/naloxone tablets according to the
invention.
8 Preparation (designation) OxN20/ OxN20/ OxN20/ OxN20/ 1-Extr-A
1-Extr-B 1-Extr-C 10-Extr-A Oxycodone 20 mg 20 mg 20 mg 20 mg HCl
Naloxone HCl 1 mg 1 mg 1 mg 10 mg Lactose Flow 58.25 mg 58.25 mg
58.25 mg 49.25 mg Lac 100 Kollidon .RTM. 30 6 mg 6 mg 6 mg 6 mg
Ethylcellulose 10 mg 10 mg 10 mg 10 mg Stearly alcohol 24 mg 24 mg
24 mg 24 mg Talcum 1.25 mg 1.25 mg 1.25 mg 1.25 mg Mg-Stearate 2.5
mg 2.5 mg 2.5 mg 2.5 mg
[0116] Extrusion was performed as described above (Example 2) with
the following parameters:
9 OxN20/1-Extr-A: temperature: 55-63.degree. C. rpm (screw): 150
rpm feeding rate: 1.5 kg/h OxN20/1-Extr-B: temperature:
55-63.degree. C. rpm (screw): 155 rpm feeding rate: 1.5 kg/h
OxN20/1-Extr-C: temperature: 55-63.degree. C. rpm (screw): 1505 rpm
feeding rate: 1.5 kg/h OxN20/10-Extr-A: temperature: 55-63.degree.
C. rpm (screw): 160 rpm feeding rate: 1.75 kg/h
[0117] Tablet production was performed with a common tabletting
device with the following parameters:
10 OxN20/1-Extr-A: rpm: 40 rpm Pressure power: 9 kN OxN20/1-Extr-B:
rpm: 42 rpm Pressure power: 8.9 kN OxN20/1-Extr-C: rpm: 36 rpm
Pressure power: 9 kN OxN20/10-Extr-A: rpm: 36 rpm Pressure power:
7.5 kN
[0118] The release of the active compounds was measured over a time
period of 12 hours, applying the Basket Method according to USP at
pH 1.3 using HPLC. Tablets OxN20/1-Extr-A, OxN20/1-Extr-B,
OxN20/1-Extr-C and OxN20/10-Extr-A were tested.
[0119] One recognizes from the values listed in the Table that in
the case of a non-swellable diffusion matrix based on
ethylcellulose, the release rates of different naloxone amounts,
independent of the oxycdone amount, remain substantially equal.
Correspondingly, the preparations provide for an independent and
invariant release of the active compounds.
11 OxN20/1- OxN20/1- OxN20/1- OxN20/10- Time Extr-A Extr-B Extr-C
Extr-A (min) Oxy Nal Oxy Nal Oxy Nal Oxy Nal 0 0 0 0 0 0 0 0 0 15
21.2 25.8 21.7 21.1 19.7 19.3 23.3 24.3 120 56.6 53.8 58.8 57.3
57.7 56.2 64.5 66.9 420 87.2 84.5 94.2 92.6 93.7 91.5 92.7 96.3 720
99.7 96.8 100.1 98 100.6 97.5 93.6 97.4
[0120] 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 92.3%. The maximal deviation at 420 min
is 7.4%. Oxy and Nal stand for oxycodone and naloxone and indicate
the active compound which has been measured.
[0121] Thus, once a preparation with the desired release profile
has been developed, one can change the amount of the active
compounds without significantly changing the release profiles of
the active compounds. The preparations comprising different amounts
of the active compounds still provide for a sustained, independent
an invariant release of the active compounds.
EXAMPLE 8
Production of Tablets with Oxycodone/Naloxone in a Non-Swellable
Diffusion Matrix by Extrusion
[0122] In the following example it is set out that using
formulations according to the present invention, preparations
comprising oxycodone and naloxone with particular release
behaviours may be obtained.
[0123] The following amounts of the listed components were used for
the production of oxycodone/naloxone tablets according to the
invention.
12 Preparation OxN20/1- OxN20/1- OxN20/10- OxN20/10- OxN20/10-
OxN20/10- (designation) Extr-D Extr-E Extr-B Extr-C Extr-D Extr-E
oxycodone HCl 20 mg 20 mg 20 mg 20 mg 20 mg 20 mg naloxone HCl 1 mg
1 mg 10 mg 10 mg 10 mg 10 mg Lactose Flow 56.25 mg 56.25 mg 54.25
mg 65.25 mg 60.25 mg 55.25 Lac 100 Kollidon .RTM. 30 7 mg 6 mg 6 mg
7.25 mg 7.25 mg 7.25 mg Ethylcellulose 11 mg 12 mg 10 mg 12 mg 12
mg 12 mg Stearyl alcohol 24 mg 24 mg 24 mg 28.75 mg 28.75 mg 28.75
mg Talcum 1.25 mg 1.25 mg 1.25 mg 1.25 mg 1.25 mg 1.25 mg
Mg-Stearate 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mg
[0124] Extrusion was performed as described above (Example 2) with
the following parameters:
13 OxN20/1-Extr-D: temperature: 55-63.degree. C. rpm (screw): 150
rpm feeding rate: 1.5 kg/h OxN20/1-Extr-E: temperature:
55-63.degree. C. rpm (screw): 150 rpm feeding rate: 1.5 kg/h
OxN20/10-Extr-B: temperature: 55-63.degree. C. rpm (screw): 160 rpm
feeding rate: 1.75 kg/h OxN20/10-Extr-C: temperature: 55-63.degree.
C. rpm (screw): 160 rpm feeding rate: 1.75 kg/h OxN20/10-Extr-D:
temperature: 55-63.degree. C. rpm (screw): 150 rpm feeding rate:
1.5 kg/h OxN20/10-Extr-E: temperature: 55-63.degree. C. rpm
(screw): 150 rpm feeding rate: 1.5 kg/h
[0125] Tablet production was performed with a common tabletting
device with the following parameters:
14 OxN20/1-Extr-D: rpm: 39 rpm Pressure power: 11 kN
OxN20/1-Extr-E: rpm: 39 rpm Pressure power: 10.5 kN
OxN20/10-Extr-B: rpm: 36 rpm Pressure power: 9.5 kN
OxN20/10-Extr-C: rpm: 36 rpm Pressure power: 7.8 kN
OxN20/10-Extr-D: rpm: 39 rpm Pressure power: 9 kN OxN20/10-Extr-E:
rpm: 39 rpm Pressure power: 7.5 kN
[0126] 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 OxN20/1-Extr-D, OxN20/1-Extr-E,
OxN20/10-Extr-B, OxN20/10-Extr-C, OxN20/10-Extr-D and
OxN20/10-Extr-E were tested.
15 OxN20/1- OxN20/1- OxN20/10- OxN20/10- OxN20/10- OxN20/10- Time
Extr-D Extr-E Extr-B Extr-C Extr-D Extr-E (min) Oxy Nal Oxy Nal Oxy
Nal Oxy Nal Oxy Nal Oxy Nal 0 0 0 0 0 0 0 0 0 0 0 0 0 15 16.6 16.2
17.4 17.2 26.1 26.8 21.8 21.9 18.5 18.2 18.4 18.2 120 47.6 46.9
49.6 49.7 71.1 73.0 61.2 61.8 52.8 52.8 53.3 53.3 420 82.7 84.5
84.6 85.7 94.3 96.6 93.2 94.7 86.3 86.3 87.2 88.2 720 95 97 95.2
95.8 94.9 97.9 96.4 97.9 94.8 94.8 95.7 96.5
[0127] The release values refer to oxycodone or naloxone (line 2)
and are given as percentages. Oxy and Nal stand for oxycodone and
naloxone and indicate the active compound which has been
measured.
[0128] The example shows that preparations with particular release
profiles may be produced if ethylcellulose and fatty alcohols are
used as the matrix-components that essentially influence the
release characteristics of the preparations. Once a preparation
with desired release characteristics has been obtained the amount
of the active compounds may be changed. The preparations will still
provide for a sustained, independent and invariant release
behaviour (see example 7).
* * * * *