U.S. patent application number 12/112937 was filed with the patent office on 2008-10-23 for sustained release compositions of drugs.
This patent application is currently assigned to Collegium Pharmaceuticals Inc.. Invention is credited to Alison B. Fleming, Jane Hirsh, Alexander M. Klibanov, Roman V. Rariy.
Application Number | 20080260819 12/112937 |
Document ID | / |
Family ID | 30119451 |
Filed Date | 2008-10-23 |
United States Patent
Application |
20080260819 |
Kind Code |
A1 |
Fleming; Alison B. ; et
al. |
October 23, 2008 |
SUSTAINED RELEASE COMPOSITIONS OF DRUGS
Abstract
A sustained release pharmaceutical composition has been
developed. The composition resists dose dumping when broken,
crushed or chewed, which enhances the safety of the dosage form
should it be accidentally or intentionally physically compromised.
In the preferred embodiment, a drug is modified to increase its
lipophilicity. In preferred embodiments the modified drug is
homogeneously dispersed within microparticles composed of a
material that is either slowly soluble or not soluble in water. In
some embodiments the drug containing microparticles coated with one
or more coating layers. The sustained release composition retards
the release of drug, even if the physical integrity of the
formulation is compromised (for example, by chewing or crushing)
and the resulting material is placed in 0.1N HCl. However, when
administered as directed, the drug is slowly released from the
composition as the composition is broken down or dissolved
gradually within the GI tract by a combination of diffusion,
surfactant action of bile acids, mechanical erosion, and in some
embodiments, enzymatic degradation.
Inventors: |
Fleming; Alison B.;
(Attleboro, MA) ; Rariy; Roman V.; (Allston,
MA) ; Hirsh; Jane; (Wellesley, MA) ; Klibanov;
Alexander M.; (Boston, MA) |
Correspondence
Address: |
PATREA L. PABST;PABST PATENT GROUP LLP
400 COLONY SQUARE, SUITE 1200, 1201 PEACHTREE STREET
ATLANTA
GA
30361
US
|
Assignee: |
Collegium Pharmaceuticals
Inc.
|
Family ID: |
30119451 |
Appl. No.: |
12/112937 |
Filed: |
April 30, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10614866 |
Jul 7, 2003 |
7399488 |
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12112937 |
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60463518 |
Apr 15, 2003 |
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60463514 |
Apr 15, 2003 |
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60443226 |
Jan 28, 2003 |
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60436523 |
Dec 23, 2002 |
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60393876 |
Jul 5, 2002 |
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Current U.S.
Class: |
424/458 ;
424/469; 424/484; 424/487 |
Current CPC
Class: |
A61K 9/145 20130101;
A61P 25/24 20180101; A61K 9/1617 20130101; A61K 9/5052 20130101;
A61P 25/26 20180101; A61K 47/12 20130101; A61K 9/50 20130101; A61P
25/20 20180101; A61K 9/4858 20130101; A61K 9/1682 20130101; A61P
25/30 20180101; A61P 25/04 20180101; A61K 31/485 20130101; A61K
9/1694 20130101; A61P 25/36 20180101; A61P 23/00 20180101; A61K
31/20 20130101; A61K 9/5084 20130101 |
Class at
Publication: |
424/458 ;
424/484; 424/487; 424/469 |
International
Class: |
A61K 9/52 20060101
A61K009/52; A61K 9/00 20060101 A61K009/00; A61K 9/26 20060101
A61K009/26 |
Claims
1. An orally administrable sustained release pharmaceutical
composition comprising a therapeutically effective amount of
microparticles consisting of (a) a lipophilic drug or lipophilic
derivative of a drug other than a drug prone to abuse and (b) one
or more carrier materials selected from the group consisting of
fats, fatty substances, waxes, wax-like substances and mixtures
thereof wherein the drug is dispersed within the one or more
carrier materials, and the release of a portion of incorporated
drug is retarded when the physical integrity of the composition is
compromised and the compromised composition is exposed to 0.1N
HCl.
2. An orally administrable sustained release pharmaceutical
composition comprising a therapeutically effective amount of
microparticles consisting of a lipophilic derivative of a drug
other than a drug prone to abuse dispersed within one or more
carrier materials which are either slowly soluble in water or
insoluble in water, wherein the release of a portion of
incorporated drug is retarded when the physical integrity of the
composition is compromised and the compromised composition is
exposed to 0.1N HCl.
3. The composition of claim 1 or 2, wherein the portion of the drug
released immediately when the physical integrity of the composition
is compromised is less than 80% of the total amount of drug
incorporated into formulation.
4. The composition of claim 1 or 2, wherein the lipophilic
derivative of a drug is a free base or a free acid of the drug.
5. The composition of claim 1 or 2, wherein the lipophilic
derivative of a drug is a salt comprising the ionized drug and a
counter-ion.
6. The composition of claim 1 or 2, wherein the lipophilic
derivative of a drug is an ester or amide formed between the drug
and a fatty acid.
7. The composition of claim 5 wherein the counter-ion is selected
from the group consisting of stearic acid, palmitic acid, myristic
acid, and mixtures thereof.
8. The composition of claim 5 wherein the counter-ion is selected
from the group consisting of methacrylic acid-methyl methacrylate
copolymers, acrylic acid polymers, crosslinked acrylic acid
polymers and carboxymethylcellulose.
9. The composition of claim 2 wherein the microparticles consist of
drug dispersed in a material selected from the group consisting of
fats, fatty substances, waxes, wax-like substances and mixtures
thereof.
10. The composition of claim 1 or 2 comprising one or more carrier
materials selected from the group consisting of stearic acid,
palmitic acid, and mixtures thereof.
11. The composition of claim 1 or 2 comprising one or more carrier
materials selected from the group consisting of beeswax, carnauba
wax, hydrogenated oil, and mixtures thereof.
12. The composition of claim 1 or 2 wherein the carrier materials
are selected from the group consisting of myristic acid, palmitic
acid, stearic acid, carnauba wax, beeswax and mixtures thereof.
13. The composition of claim 2 wherein the microparticles consist
of a drug dispersed in a carrier material selected from the group
consisting of naturally water insoluble proteins, naturally water
insoluble polysaccharides, naturally water insoluble lipids and
phospholipids, cross-linked water soluble proteins, cross-linked
water soluble polysaccharides and combinations thereof.
14. The composition of claim 1 or 2 wherein the individual
microparticles are coated with one or more independent layers.
15. The composition of claim 14 wherein the coated layer(s)
comprise a material selected from the group consisting of naturally
water insoluble proteins, naturally water insoluble
polysaccharides, naturally water insoluble lipids and
phospholipids, cross-linked proteins, cross-linked polysaccharides,
mixtures of waxes and fatty substances, and combinations
thereof.
16. The composition of claim 15 wherein the coated layer(s)
comprise a material selected from the group of pH dependent
coatings, water insoluble diffusion barrier coatings, water soluble
coatings and combinations thereof.
17. The composition of claim 1 or 2 wherein the lipophilic
derivative is dissolved in the carrier material in a molten state
to result in a uniform dispersion within the carrier material.
18. The composition of claim 1 or 2 wherein the lipophilic
derivative is dissolved in a co-solvent along with a carrier
material to result in a uniform dispersion within the carrier
material.
19. The composition of claim 1 or 2, wherein the individual
microparticles are further formulated into a tablet or capsule for
oral administration.
20. The composition of claim 19, wherein the individual
microparticles contain one or more drugs.
21. The composition of claim 19, wherein the tablet or capsule
further comprises one or more drugs formulated as an immediate
release dose, a sustained release dose, a delayed release dose, or
a combination thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation-in-Part of U.S. Ser. No.
10/614,866 filed on Jul. 7, 2003 entitled "Abuse-Deterrent
Pharmaceutical Compositions of Opiods and Other Drugs", which
claims priority to U.S. Ser. No. 60/393,876 filed Jul. 5, 2002
entitled "Abuse-Resistant Formulations of Oxycontin and Other
Drugs" by Alexander M. Klibanov, Stephen L. Buchwald, Timothy M.
Swager, and Whe-Yong Lo; U.S. Ser. No. 60/436,523 filed Dec. 23,
2002 by Alison B. Fleming, Roman V. Rariy, Alexander M. Klibanov,
Whe-Yong Lo, and Jane Hirsh; U.S. Ser. No. 60/443,226 filed Jan.
28, 2003 by Jane Hirsh, Alison B. Fleming, Alexander M. Klibanov,
and Whe-Yong Lo; U.S. Ser. No. 60/463,514 filed Apr. 15, 2003 by
Jane C. Hirsh, Alison B. Fleming, Roman V. Rariy, Stephen L.
Buchwald, and Timothy M. Swager; and U.S. Ser. No. 60/463,518 filed
Apr. 15, 2003 by Jane C. Hirsh, Alison B. Fleming and Roman V.
Rariy. The disclosures in the applications listed above are herein
incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] The present invention is generally in the field of
pharmaceutical compositions, and specifically relates to
compositions that are designed to provide a sustained release of
drug over time after oral administration.
[0003] Sustained release pharmaceutical formulations, which release
drug over an extended period of time, are widely used in the
pharmaceutical industry. Such formulations provide several
potential advantages to the patient including: (1) the convenience
of reduced dosing frequency, (2) optimization of therapy by
providing a smoother, more constant, plasma level of drug, and (3)
a potential reduction in side effects.
[0004] Several formulations that achieve sustained release of drug
when administered orally have been described in the literature. In
general, oral sustained release dosage forms can be classified as
diffusion-controlled, erosion-controlled or osmotic
pressure-controlled. For diffusion based systems, control of drug
release is usually achieved by dispersing the drug in an inert
insoluble matrix or by coating a drug containing core with an
insoluble polymeric film. Erosion controlled formulations can be
achieved by dispersing the drug in a slowly soluble carrier
material or by coating the drug with a slowly soluble material.
Osmotic systems are monolithic in nature and consist of a core
containing an osmotically active drug or a drug in combination with
an osmotically active salt, surrounded by a semi-permeable membrane
containing a small orifice.
[0005] Although many types of sustained release dosage forms have
been described, currently available sustained release dosage forms
have some inherent disadvantages. Monolithic dosage forms, such as
tablets or capsules, can be difficult for some patients to swallow.
Since sustained release formulations can be subject to dose dumping
when they are crushed, these products come with specific
instructions not to break, chew or crush them. While there are some
available multiparticulate formulations (such as
particles-in-capsule and sachet) that can be administered as
particles, for example after sprinkling in applesauce, such
formulations are still potentially dangerous if the particles are
accidentally chewed, broken or their physical integrity is
compromised, thus resulting in the destruction of the sustained
release feature.
[0006] It is therefore an object of the present invention to
provide a sustained-release, multiparticulate pharmaceutical
composition that resists dose dumping when accidentally broken,
crushed or chewed.
SUMMARY OF THE INVENTION
[0007] Sustained release pharmaceutical compositions and the
methods of making and using the composition have been developed.
The compositions can be used to improve the convenience and safety
of administration when a sustained release dosage form is desired.
In the preferred embodiment, the drug is chemically modified to
increase its lipophilicity. In other embodiments, the formulation
contains lipophilic or water-insoluble materials or is made using a
process which increases the lipophilicity and/or water-insolubility
of the composition. In some embodiments, the individual
drug-containing microparticles or drug particles are coated with
one or more independent coating layers.
[0008] The compositions retard the release of drug, even if the
physical integrity of the dosage form is compromised (for example,
by breaking or chewing).
[0009] The pharmaceutical compositions, when administered orally,
result in a desired drug release profile. Such a release profile
provides a therapeutic effect for an extended period of time,
typically from 6 to 24 hours. Additional compositions are provided
which achieve a small immediate dose that precedes the sustained
release of drug. The compositions disclosed herein may optionally
include a combination of active pharmaceutical agents.
DETAILED DESCRIPTION OF THE INVENTION
[0010] Disclosed herein are sustained-release pharmaceutical
compositions and the method of making and using the
compositions.
I. Compositions
[0011] As used herein, "composition" or "compositions" refers to
the drug dosage unit for administration to a patient. This may also
be used in reference to the final dosage form (tablet or capsule)
or to components of the final dosage form (microparticles or coated
microparticles).
[0012] Currently available sustained release formulations are
subject to dose dumping when chewed or crushed because mechanical
destruction of the dosage form exposes the encapsulated drug and
allows for immediate dissolution of the drug into aqueous media.
Two properties of the dosage form that contribute to this outcome
are (1) the ease with which drug is exposed when the compositions
are broken or chewed and (2) the high water solubility of the drug
salt form.
[0013] In the composition disclosed herein, one or both of these
properties are altered in order to achieve a composition which
resists dose dumping when chewed or broken. Specifically, in the
preferred embodiment, the drug is modified to increase its
lipophilicity and, in additional preferred embodiments, is then
homogeneously dispersed within a material that is either slowly
soluble or not soluble in water and subsequently formulated into
microparticles. The drug may be present in the form of discrete
particles or may be partially or fully dispersed in the carrier
material on a molecular level.
[0014] The sustained release composition preferably includes a drug
modified to increase its lipophilicity. In other preferred
embodiments, the drug is homogenously dispersed within
microparticles composed of a material that is either slowly soluble
in water or water insoluble. The compositions slow the release of
drug if the dosage form is broken or chewed and the resulting
material is swallowed since most of the drug will remain associated
with or entrapped within portions of the core material of the
microparticles. In some embodiments the drug containing
microparticles or individual drug particles are coated with one or
more coating layers.
[0015] A. Drugs to be Formulated
[0016] There are many drugs that it is desirable to deliver using
the compositions described herein.
[0017] Exemplary drug agents useful for forming the composition
described herein include, but are not limited to, analeptic agents;
analgesic agents; anesthetic agents; antiasthmatic agents;
antiarthritic agents; anticancer agents; anticholinergic agents;
anticonvulsant agents; antidepressant agents; antidiabetic agents;
antidiarrheal agents; antiemetic agents; antihelminthic agents;
antihistamines; antihyperlipidemic agents; antihypertensive agents;
anti-infective agents; antiinflammatory agents; antimigraine
agents; antineoplastic agents; antiparkinsonism drugs; antipruritic
agents; antipsychotic agents; antipyretic agents; antispasmodic
agents; antitubercular agents; antiulcer agents; antiviral agents;
anxiolytic agents; appetite suppressants; attention deficit
disorder and attention deficit hyperactivity disorder drugs;
cardiovascular agents including calcium channel blockers,
antianginal agents, central nervous system ("CNS") agents,
beta-blockers and antiarrhythmic agents; central nervous system
stimulants; diuretics; genetic materials; hormonolytics; hypnotics;
hypoglycemic agents; immunosuppressive agents; muscle relaxants;
narcotic antagonists; nicotine; nutritional agents;
parasympatholytics; peptide drugs; psychostimulants; sedatives;
steroids; smoking cessation agents; sympathomimetics;
tranquilizers; vasodilators; beta-agonist; and tocolytic
agents.
[0018] Drugs that are most preferable include those that are
currently formulated as sustained or controlled release
compositions, where drug release is intended to occur over a
prolonged period of time through the gastrointestinal tract, and
immediate or burst release is undesirable. Specific examples of
agents currently formulated in sustained or controlled release
formulations include, but are not limited to, acetaminophen,
acetazolamide, albuterol, alfuzosin, alprazolam, amoxicillin,
amphetamine, aspirin, brompheniramine, bupropion, carbamazepine,
carbidopa, carbinoxamine, cetirizine, chlorpheniramine,
ciprofoxacin, clarithromycin, clavulanate, clorazepate, colestipol,
desloratidine, dexbrompheniramine, dexmethylphenidate,
dextroamphetamine, dextromethorphan, diclofenac, diethylpropion,
diltiazem, dipyridamole, disopyramide, divalproex sodium,
doxazosin, doxycycline, enalapril, etodolac, felodipine,
fexofenadine, fluoxetine, fluvastatin, glipizide, guaifenesin,
hyoscyamine, indomethacin, isosorbide dinitrate, isosorbide
mononitrate, isradipine, ketoprofen, levodopa, loratidine,
lovastatin, mesalamine, metformin, methscopolamine,
methylphenidate, metoprolol, metronidazole, minocycline, morphine,
naproxen, niacin, nicardipene, nifedipine, nsoldipine,
nitroglycerin, orphenadrine, oxybutynin, oxycodone, oxymorphone,
papaverine, paroxetine, pentoxifyline, phendimetrazine,
phenylephrine, phenyloin, procainamide, propranolol,
pseudophedrine, pyridostigime, quinidine, ranolazine, tamsulosin,
theophylline, tolterodine, tramadol, trandolapril, venlafaxine,
verapamil, and zolpidem.
[0019] The terms "drug", "active agent", and "pharmacologically
active agent" are used interchangeably herein to refer to a
chemical compound that induces a desired pharmacological and/or
physiological effect. The terms also encompass pharmaceutically
acceptable derivatives of those active agents specifically
mentioned herein, including, but not limited to, salts, solvates,
hydrates, complexes with one or more molecules, prodrugs, active
metabolites, analogs, and the like. When the terms "active agent",
"pharmacologically active agent" and "drug" are used, or when a
particular drug, such as oxycodone, is identified, it is to be
understood as including the active agent per se as well as
pharmaceutically acceptable salts, solvates, hydrates, complexes
with one or more molecules, prodrugs, active metabolites, and
analogs.
[0020] Certain compounds described herein may exist in particular
geometric or stereoisomeric forms. The composition disclosed herein
contemplates all such compounds, including cis- and trans-isomers,
R- and S-enantiomers, diastereomers, d-isomers, 1-isomers, the
racemic mixtures thereof, compounds of different spacial
conformations, and other mixtures thereof, as falling within the
scope of the invention. Additional asymmetric carbon atoms may be
present in a substituent such as an alkyl group. All such isomers,
as well as mixtures thereof, are intended to be included in this
invention.
[0021] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines;
alkali or organic salts of acidic residues such as carboxylic
acids; and the like. The pharmaceutically acceptable salts include
the conventional non-toxic salts or the quaternary ammonium salts
of the parent compound formed, for example, from non-toxic
inorganic or organic acids.
[0022] The pharmaceutically acceptable salts of the compounds can
be synthesized from the parent compound, which contains a basic or
acidic moiety, by conventional chemical methods. Generally, such
salts can be prepared by reacting the free acid or base forms of
these compounds with a stoichiometric amount of the appropriate
base or acid in water or in an organic solvent, or in a mixture of
the two; generally, non-aqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile are preferred. Optionally,
the salt can also be formed as part of the manufacturing process
for the composition. For fatty acid salts such as oleate,
myristate, palmitate or stearate, this can be accomplished by
melting the fatty acid, optionally along with other waxes, and
adding the free base of the drug directly into this melt. Lists of
suitable salts are found in Remington's Pharmaceutical Sciences,
20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000,
p. 704, the disclosure of which is hereby incorporated by
reference.
[0023] Optionally, the composition described herein can include a
combination of active pharmaceutical agents.
[0024] B. Drug Solubility Modification
[0025] In preferred embodiments, the solubility characteristics of
a drug are altered prior to incorporation into the formulation.
Modification of the drug to produce a more lipophilic derivative
serves to reduce the water solubility of the drug and thus reduces
the aqueous extractability. Furthermore, if the drug is made more
lipophilic, it can be solubilized in the molten carrier material,
rather than physically dispersed in a particulate form. When drug
is solubilized in the carrier material it is difficult to extract
drug from the resulting intimately dispersed composition.
[0026] The terms "lipophilic derivative" and "lipophililic drug
derivative", as used herein, refer to derivatives of the drug that
are less soluble in water than the most soluble salt of the drug.
The most soluble salt is selected from either drug alkaline metal
salts (for acidic drugs) or salts of the drug with inorganic acids
(for basic drugs). The examples of the latter include, but are not
limited to, hydrohalates, sulfates, and nitrates.
[0027] Some of the methods that can be used to alter the drug's
lipophilicity are outlined below. It is understood that two or more
approaches can be combined to achieve a desired solubility
profile.
[0028] Methods for Increasing Lipophilicity
[0029] In one embodiment drug is made more lipophilic by
eliminating or reducing the overall charge of the drug molecule.
For example, for a basic drug, a water soluble salt (such as
hydrochloride, sulfate, or maleate) can be converted to a free base
using techniques known in the art. Correspondingly, in the case of
an acidic drug, a water soluble salt (such sodium, potassium, or
the like) can be converted to a free acid.
[0030] In another embodiment, the drug's lipophilicity is increased
by forming a salt between a drug molecule and a charged compound.
In this case the lipophilicity, or water solubility, of the
resulting salt can be manipulated by varying the counter-ion. In
general, lipophilic acids or amines with chain lengths between
C.sub.5-C.sub.30 are lipophilic counter-ion candidates. Some
specific examples include, but are not limited to, linoleic acid,
octanoic acid, lauric acid, stearic acid, palmitic acid, lauryl
sulfate, oleic acid, octyl amine, lauryl amine, stearyl amine,
palmityl amine, linoleyl amine, and oleyl amine. Other salts which
may increase lipophilicity and, hence, lipid solubility relative to
the parent drug compound include, but are not limited to,
pectinate, tannate, phytate, salicylate, saccharinate,
acesulfamate, gallate, and terephthalate salts. The counter-ion
used for salt formation may also be polymeric in nature. For
example, anionic copolymers based on methacrylic acid and methyl
methacrylate sold under the trade name Eudragit (e.g., Eudragit L
100 and Eudragit S 100), acrylic acid polymers, and crosslinked
acrylic acid polymers may be used to form a salt with drug
molecules. Naturally occurring polymers and their derivatives, for
example, carboxymethylcellulose, may also be used to form a salt
with the drug molecules. In the case of polymeric counter-ions, the
number of drug molecules reacted with the polymer to form a salt
may or may not be equimolar with respect to the number of
salt-forming sites on the polymer chain.
[0031] The formation of a salt composed of a pharmaceutically
active agent and a fatty acid or amine can be accomplished by a
melt process, with or without the use of a solvent. One or more
fatty acids or amines are heated above their melting point and the
pharmaceutically active agent, in free base or acid form, is added
to the molten fatty acid or amine, respectively, either directly or
after dissolution of the active agent in an appropriate solvent.
The fatty acid or fatty amine may be present in an equimolar amount
or may be present in excess with respect to the free base or free
acid of the active agent.
[0032] In another embodiment, a drug is covalently modified to
increase its lipophilicity. For example, a lipophilic compound can
be covalently attached to a drug molecule via an ester or amide
linkage. Such drug derivatives are cleaved in vivo, thus releasing
the parent compound.
[0033] C. Drug Containing Microparticles
[0034] In preferred embodiments, drugs are formulated with a
carrier material to form microparticles. As used herein, the term
"microparticle" refers to a composition including a drug dispersed
within a carrier material and "coated microparticle" refers to a
composition including a drug containing microparticle or a drug
particle coated with one or more coating layers of material.
Microparticles and coated microparticles have a size range of 10 to
3000 microns in diameter.
[0035] Within microparticles, drug is preferably homogeneously
dispersed in the form of fine particles within the carrier
material. More preferably, drug is partially solubilized in molten
carrier material or partially dissolved with the carrier material
in a mutual solvent during the formulation of the microparticles.
Most preferably, drug is completely solubilized in the molten
carrier material or completely dissolved with the carrier material
in a co-solvent during the formulation of the microparticles. This
is accomplished through the selection of materials and the manner
in which they are processed.
[0036] Carrier materials appropriate for the fabrication of drug
containing microparticles are either slowly soluble in water or
insoluble in water, but capable of degrading within the GI tract by
means including enzymatic degradation, surfactant action of bile
acids and mechanical erosion. As used herein, the term "slowly
soluble in water" refers to materials that are not dissolved in
water within a period of 30 minutes. Preferred examples include
fats, fatty substances, waxes, wax-like substances and mixtures
thereof. Suitable fats and fatty substances include fatty alcohols
(such as lauryl, myristyl stearyl, cetyl or cetostearyl alcohol),
fatty acids and derivatives, including but not limited to fatty
acid esters, fatty acid glycerides (mono-, di- and tri-glycerides),
and hydrogenated fats. Specific examples include, but are not
limited to hydrogenated vegetable oil, hydrogenated cottonseed oil,
hydrogenated castor oil, hydrogenated oils available under the
trade name Sterotex.RTM., stearic acid, cocoa butter, glyceryl
behenate (available under the trade name COMPRITOL 888.RTM.),
glyceryl dipalmitostearate (available under the trade name
PRECIROL.RTM.), and stearyl alcohol. Mixtures of mono-, di- and
tri-glycerides and mono- and di-fatty acid esters of polyethylene
glycol, available under the trade name GELUCIRE.RTM.) are also
suitable fatty materials. Suitable waxes and wax-like materials
include natural or synthetic waxes, hydrocarbons, and normal waxes.
Specific examples of waxes include beeswax, glycowax, castor wax,
carnauba wax, paraffins and candelilla wax. As used herein, a
wax-like material is defined as any material which is normally
solid at room temperature and has a melting point of from about 30
to 300.degree. C.
[0037] In some cases, it may be desirable to alter the rate of
water penetration into the hydrophobic drug containing
microparticles. To this end, rate-controlling (wicking) agents may
be formulated along with the fats or waxes listed above. Examples
of rate-controlling materials include certain starch derivatives
(e.g., waxy maltodextrin and drum dried corn starch), cellulose
derivatives (e.g., hydroxypropylmethylcellulose,
hydroxypropylcellulose, methylcellulose, and
carboxymethylcellulose), alginic acid, lactose and talc.
Additionally, a pharmaceutically acceptable surfactant (for
example, lecithin) may be added to facilitate the degradation of
such microparticles.
[0038] Proteins which are water insoluble, such as zein, are
preferred carrier materials for the formation of drug containing
microparticles. Additionally, proteins, polysaccharides and
combinations thereof which are water soluble can be formulated with
drug into microparticles and subsequently cross-linked to form an
insoluble network.
[0039] Certain polymers may also be used as carrier materials in
the formulation of drug containing microparticles. Suitable
polymers include ethylcellulose and other natural or synthetic
cellulose derivatives. Polymers which are slowly soluble and form a
gel in an aqueous environment, such as hydroxypropyl
methylcellulose or polyethylene oxide may also be suitable as
carrier materials for drug containing microparticles.
[0040] Encapsulation or incorporation of drug into carrier
materials to produce drug containing microparticles can be achieved
through known pharmaceutical formulation techniques. To create a
composition that protects drug from exposure upon mechanical
disruption (e.g., breaking or chewing), the drug is intimately
dispersed within the carrier material. In the case of formulation
in fats, waxes or wax-like materials, the carrier material is
heated above its melting temperature and the drug is added to form
a mixture including drug particles suspended in the carrier
material, drug dissolved in the carrier material, or a mixture
thereof. Microparticles can be subsequently formulated through
several methods including, but not limited to, the processes of
congealing, extrusion, spray chilling or aqueous dispersion. In a
preferred process, wax is heated above its melting temperature,
drug is added, and the molten wax-drug mixture is congealed to form
solid, spherical particles via a spraying or spinning disk process.
Alternatively, the molten wax-drug mixture can be extruded and
spheronized to form pellets or beads. Detailed descriptions of
these processes can be found in "Remington--The science and
practice of pharmacy", 20.sup.th Edition, Jennaro et. Al., (Phila,
Lippencott, Williams, and Wilkens, 2000. Detailed descriptions of
the spinning disk process can be found in U.S. Pat. Nos. 3,015,128
and 7,261,529.
[0041] For some carrier materials it may be desirable to use a
solvent evaporation technique to produce drug containing
microparticles. In this case drug and carrier material are
co-dissolved in a mutual solvent and microparticles can
subsequently be produced by several techniques including, but not
limited to, forming an emulsion in water or other appropriate
media, spray drying, using a spinning disk process or by
evaporating off the solvent from the bulk solution and milling the
resulting material.
[0042] In addition to modification of the drug itself, processing
conditions can be used to influence the dispersion of the drug
within water-insoluble or slowly water-soluble material. For
example, in the case where the water in-soluble or slowly soluble
material is melted and drug is fully or partially dissolved under
stirring conditions, the temperature, agitation rate and time of
processing will influence the degree of dissolution achieved. More
specifically, a more homogenous dispersion may be achieved with a
higher temperature, faster stirring rate and longer processing
time. Ultrasound can also be applied to the molten mixture to
increase the degree of dispersion and/or the rate of dissolution of
the drug.
[0043] In some embodiments, drug in a particulate form is
homogeneously dispersed in a water-insoluble or slowly water
soluble material. To minimize the size of the drug particles within
the composition, the drug powder itself may be milled to generate
fine particles prior to formulation. The process of jet milling,
known in the pharmaceutical art, can be used for this purpose. In
some embodiments drug in a particulate form is homogeneously
dispersed in a wax or wax like substance by heating the wax or wax
like substance above its melting point and adding the drug
particles while stirring the mixture. In this case a
pharmaceutically acceptable surfactant may be added to the mixture
to facilitate the dispersion of the drug particles.
[0044] For formulations including a pharmaceutically active agent
in the free base form and one or more fatty acids, a homogeneous
molten mixture, in which the drug particles are completely
dissolved, can be achieved in the following manner. The one or more
fatty acid(s) are heated above their melting point but below the
melting point of the active agent. The active agent in free base
form is mixed with the molten fatty acid until a clear, homogeneous
mixture is formed. The active agent may be added in the solid form
or may first be dissolved in an appropriate solvent. Optionally,
one or more fats, fatty substances, waxes, and/or wax-like
substances are co-melted into the mixture, either before the
addition of the active agent or following the addition of the
active agent. It is believed that a clear solution is formed due to
the formation of a salt between the free base of the active agent
and the one or more fatty acids present in the formulation. An
analogous composition may be formed using the free acid of the
active agent, one or more fatty amines, and, optionally, one or
more fats, fatty substances, waxes, and/or wax-like substances.
[0045] D. Coated Drug Containing Microparticles
[0046] In some embodiments, drug containing microparticles or drug
particles are encapsulated. Drug containing microparticles can be
encapsulated in water insoluble materials, slowly water soluble
materials, or materials with pH dependent solubilities.
[0047] In general, any coating procedure which provides a
contiguous coating on each microparticle without significant
agglomeration of particles may be used. Coating procedures known in
the pharmaceutical art including, but not limited to, fluid bed
coating processes and microencapsulation may be used to obtain
appropriate coatings. Detailed descriptions of these processes can
be found in "Remington--The science and practice of pharmacy",
20.sup.th Edition, Jennaro et. Al., (Phila, Lippencott, Williams,
and Wilkens, 2000.
[0048] The water-insoluble coating materials may be any of a large
number of natural or synthetic film-formers used singly, in
admixture with each other, and in admixture with plasticizers,
pigments and other substances to alter the characteristics of the
coating. A water-insoluble but water-permeable diffusion barrier
may consist of ethyl cellulose, methyl cellulose and mixtures
thereof. The water-permeable diffusion barrier may also include
ammonio methacrylate copolymers sold under the trade name
EUDRAGIT.RTM. (Rohm Pharma), such as EUDRAGIT RS, EUDRAGIT RL,
EUDRAGIT NE and mixtures thereof. Other synthetic polymers, for
example, polyvinyl acetate (available under the trade name
KOLLICOAT.RTM.), can also be used to form water-insoluble but
permeable coatings.
[0049] The coating may also include a water-insoluble but
enzymatically degradable material. In some instances the substrates
of digestive enzymes are naturally water-insoluble and can be
utilized in the formulation without further processing. Solid
esters of fatty acids, which are hydrolyzed by lipases, can be
spray coated onto microparticles or drug particles. Mixtures of
waxes (beeswax, carnauba wax, etc.) with glyceryl monostearate,
stearic acid, palmitic acid, glyceryl monopalmitate and cetyl
alcohol will also form films that are dissolved slowly or broken
down in the GI tract. Zein is an example of a naturally
water-insoluble protein. It can be coated onto drug containing
microparticles or drug particles by spray coating or by wet
granulation techniques. In addition to naturally water-insoluble
materials, some substrates of digestive enzymes can be treated with
cross-linking procedures, resulting in the formation of non-soluble
networks. Many methods of cross-linking proteins, initiated by both
chemical and physical means, have been reported. One of the most
common methods to obtain cross-linking is the use of chemical
cross-linking agents. Examples of chemical cross-linking agents
include aldehydes (gluteraldehyde and formaldehyde), epoxy
compounds, carbodiimides, and genipin. In addition to these
cross-linking agents, oxidized and native sugars have been used to
cross-link gelatin (Cortesi, R., et al., Biomaterials 19 (1998)
1641-1649). Cross-linking can also be accomplished using enzymatic
means; for example, transglutaminase has been approved as a GRAS
substance for cross-linking seafood products. Finally,
cross-linking can be initiated by physical means such as thermal
treatment, UV irradiation and gamma irradiation.
[0050] To produce a coating layer of cross-linked protein
surrounding drug containing microparticles or drug particles, a
water soluble protein can be spray coated onto the microparticles
and subsequently cross-linked by the one of the methods described
above. Alternatively, drug containing microparticles can be
microencapsulated within protein by coacervation-phase separation
(for example, by the addition of salts) and subsequently
cross-linked. Some suitable proteins for this purpose include
gelatin, albumin, casein, and gluten.
[0051] Polysaccharides can also be cross-linked to form a
water-insoluble network. For many polysaccharides, this can be
accomplished by reaction with calcium salts or multivalent cations
which cross-link the main polymer chains. Pectin, alginate,
dextran, amylose and guar gum are subject to cross-linking in the
presence of multivalent cations. Complexes between oppositely
charged polysaccharides can also be formed; pectin and chitosan,
for example, can be complexed via electrostatic interactions.
Insoluble coatings can be formed on particles in this fashion. It
should be noted that in many cases polysaccharides are broken down
specifically by enzymes produced by bacteria within the colon.
[0052] In some cases a water-insoluble but enzymatically degradable
coating including both a protein and a polysaccharide can be
produced if the components are oppositely charged polyelectrolytes.
Under the proper temperature, pH, and concentrations, the two
polymers can interact through their opposite electrical charges and
form a water-insoluble complex. If a core particle is present at
the time the complex phase separates, it will be coated. For
example, gelatin and gum arabic can be coated onto a core particle
utilizing this process. Optionally, the complex can be made
irreversibly insoluble by subsequent cross-linking induced by
chemical or physical means.
[0053] Coating materials may also include a pH sensitive polymer
which is insoluble in the acid environment of the stomach, and
soluble in the more basic environment of the GI tract. Such a
coating is thus an enteric coating, creating a dosage form designed
to prevent drug release in the stomach. Preventing drug release in
the stomach has the advantage of reducing side effects associated
with irritation of the gastric mucosa, and of minimizing exposure
of drug to very low pH. Avoiding release within the stomach can be
achieved using enteric coatings known in the art. The enteric
coated formulation remains intact or substantially intact in the
stomach, however, once the formulation reaches the small
intestines, the enteric coating dissolves and exposes either
drug-containing carrier particles or drug-containing carrier
particles coated with extended release coating.
[0054] The enteric coated particles can be prepared as described in
"Pharmaceutical dosage form tablets", eds. Liberman et. al. (New
York, Marcel Dekker, Inc., 1989), "Remington--The science and
practice of pharmacy", 20th ed., Lippincott Williams & Wilkins,
Baltimore, Md., 2000, and "Pharmaceutical dosage forms and drug
delivery systems", 6th Edition, Ansel et. al., (Media, Pa. Williams
and Wilkins, 1995). Examples of suitable coating materials include,
but are not limited to, cellulose polymers, such as cellulose
acetate phthalate, hydroxypropyl cellulose, hydroxypropyl
methylcellulose phthalate and hydroxypropyl methylcellulose acetate
succinate; polyvinyl acetate phthalate, acrylic acid polymers and
copolymers, and certain methacrylic resins that are commercially
available under the trade name EUDRAGIT.RTM. (Rohm Pharma).
Additionally the coating material may contain conventional carriers
such as plasticizers, pigments, colorants, glidants, stabilization
agents, and surfactants.
[0055] In some cases it may be desirable to coat the particles with
a coating which is soluble in aqueous solutions but insoluble in
hydroalcoholic solutions. In this case the coating material may or
may not have pH sensitive solubility in aqueous solutions.
[0056] In some cases it may be desirable to combine coating
materials to produce a tailored release of drug. For example,
combinations of insoluble polymers and pH dependent polymers can
produce a pH dependent sustained release profile. Combinations of
insoluble polymers (e.g., ethylcellulose), water-soluble polymers
(e.g., HPMC or PEG) and pH dependent swellable polymers (e.g.,
carboxyvinylpolymer) have also been reported to produce pH
dependent sustained release profiles (See, for example, Journal of
Controlled Release, 2006, 111:309-315)
[0057] E. Dosage Forms
[0058] There are a number of drug compositions that meet the
criteria outlined above. In one embodiment a drug is homogeneously
dispersed, in a fine particulate form, within a water-insoluble or
slowly water soluble material and the mixture is formulated into
microparticles. In another embodiment a drug is partially dissolved
within a water-insoluble or slowly water soluble material during
the manufacturing process, for example, by mixing at a temperature
above the melting point of the carrier material, and the mixture is
formulated into microparticles. In yet another embodiment a drug is
fully dissolved within a water-insoluble or slowly water soluble
material during the manufacturing process, for example, by mixing
at a temperature above the melting point of the carrier material,
and the mixture is formulated into microparticles. In still a
further embodiment, the drug containing microparticles, where the
drug is homogeneously dispersed in a particulate form, or has been
partially or fully dissolved within the carrier material during the
manufacturing process, are coated with one or more coatings to form
coated microparticles.
[0059] The microparticles, coated microparticles, or a mixture
thereof are formed into a solid dosage form suitable for oral
administration. For example, microparticles or coated
microparticles can be incorporated into hard capsules, dispersed
within a soft gelatin capsule, or combined with appropriate
excipients and tableted by compression.
[0060] Dosage forms can include one or more drugs. If the drugs are
compatible, several different drugs can be incorporated into the
same microparticle composition or coated microparticle composition.
The drugs can be incorporated into separate microparticle
compositions where a first drug is formulated into microparticle
compositions or coated microparticle compositions described herein
and one or more additional drugs are incorporated into
microparticle compostions or coated microparticle compositions
described herein, sustained release compositions known in the art
or immediate release compositions known in the art. The
compositions including the different drugs are formulated into a
single solid dosage form suitable for oral administration, for
example, they can be incorporated into a gelatin capsule, or
combined with appropriate excipients and compressed into a tablet
form.
[0061] An immediate release dose can be incorporated into the
formulation in several ways. Immediate release microparticles can
be made utilizing standard methodologies and formulated along with
sustained release microparticle and/or coated microparticle
compositions in a suitable oral dosage form. Alternatively, a
coating containing drug which is available for immediate release
can be placed on a tablet including sustained release microparticle
and/or coated microparticle compositions plus appropriate
excipients. Additionally, an immediate dose of drug can be
granulated or blended with rapidly dissolving excipients and
subsequently compressed (1) as one layer of bi-layer tablets in
which the sustained release microparticle and/or coated
microparticle compositions are compressed as the other layer, or
(2) as the outer layer of compression-coated tablets in which the
sustained release microparticle and/or coated microparticle
compositions are compressed as the inner core, or (3) into tablets
in which sustained release microparticle and/or coated
microparticle compositions are embedded.
[0062] Optional excipients present in the oral dosage form
including abuse deterrent microparticles or coated microparticles
include, but are not limited to diluents, binders, lubricants,
disintigrants, colorants, plasticizers and the like. Diluents, also
termed "fillers," are typically necessary to increase the bulk of a
solid dosage form so that a practical size is provided for
compression of tablets. Examples of diluents include cellulose, dry
starch, microcrystalline cellulose, dicalcium phosphate, calcium
sulfate, sodium chloride confectioner's sugar, compressible sugar,
dextrates, dextrin, dextrose, sucrose, mannitol, powdered
cellulose, sorbitol, and lactose. Binders are used to impart
cohesive qualities powdered materials and can include materials
such as starch, gelatin, sugars, natural and synthetic gums,
polyethylene glycol, ethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose, waxes and
polyvinyl pyrrolidone. Lubricants are used to facilitate tablet
manufacture; examples of lubricants include talc, magnesium
stearate, calcium stearate, hydrogenated vegetable oils stearic
acid, sodium stearyl fumarate, sodium benzoate, sodium acetate,
leucine, sodium oleate, sodium lauryl sulfate, magnesium lauryl
sulfate and polyethylene glycol. Disintegrants can be added to
pharmaceutical formulations in order to facilitate "breakup" or
disintegration after administration. Materials used for this
purpose include starches, clays, celluloses, aligns, gums, and
cross-linked polymers. A plasticizer may be included in coating
materials to alter their mechanical properties. Examples of
plasticizers include benzyl benzoate, chlorobutanol, dibutyl
sebacate, diethyl phthalate, glycerin, mineral oil, polyethylene
glycol, sorbitol, triacetin, triethyl citrate, glycerol, etc. In
addition to the additives above, coloring and flavoring agents may
also be incorporated into the composition.
II. Methods of Administration
[0063] It is assumed that upon oral ingestion of the intact
composition, drug is released as the formulation is gradually
broken down or dissolved within the GI tract by a combination of
diffusion, surfactant action of bile acids, mechanical erosion,
and, in some embodiments, enzymatic degradation. This is a result
of the unique ability of the human digestive system to efficiently
break down or solubilize a variety of materials. The process within
the GI tract that results in the digestion of food and the
absorption of nutrients is well known. Following mastication within
the mouth, food passes into the stomach where it is mixed with
digestive juices. This fluid contains the proteolytic enzyme pepsin
which, following activation by the low pH within the stomach,
begins the process of cleaving ingested proteins into smaller
peptide fragments. Food then enters the small intestine in the form
of macromolecular aggregates, where it is digested into molecules
near or in a form capable of being absorbed. This digestion is
accomplished through the action of various enzymes which are
produced in the pancreas and flow into the upper portion of the
large intestine, the duodenum. The enzymes synthesized in the
pancreas include proteases, amylases and lipases; these enzymes are
capable of breaking down proteins, starches and fats, respectively.
The digestion of fats is further facilitated by the secretion of
bile into the duodenum since bile salts, which contain both
hydrophobic and hydrophilic portions, are capable of emulsifying
lipids into minute droplets in order to increase the surface area
available for digestion by lipases. The material which remains
following passage through the small intestine enters the large
intestine. Bacteria capable of breaking down carbohydrates not
digested in the small intestine (such as cellulose) are present in
large numbers this region of the digestive tract. Finally, in
addition to microbial fermentation, the large intestine functions
to absorb water and electrolytes and to form and store feces until
they are excreted.
[0064] In some embodiments, an immediate release of drug is
achieved within the stomach in order to provide rapid therapeutic
onset.
[0065] The pharmaceutical drug composition is administered orally.
The appropriate dosage formulations can be obtained by calculation
of the pharmacokinetics of the formulation, then adjusting using
routine techniques to yield the appropriate drug levels based on
the approved dosage forms. Any suitable amount of drug containing
microparticles or coated microparticles can be included in the
final formulation. The selection of a suitable amount of drug
containing microparticles depends on the dosage desired and is
readily determined by those skilled in the art.
[0066] In addition to oral administration, some embodiments may
also be administered by other routes, including, but not limited
to, rectal and nasal administration. Some embodiments may also be
suitable for formulation as oral liquids.
[0067] The present composition and method of making and using the
composition will be further understood by reference to the
following non-limiting examples.
EXAMPLE 1
Preparation of Lipophilic Oxycodone Derivative
Oxycodone Free Base
[0068] The free base of oxycodone can be prepared from its
hydrochloride salt by the following method: Oxycodone hydrochloride
is dissolved in water and sodium carbonate was added in the amount
required to neutralize hydrochloric acid. Methylene chloride is
added in order to extract the formed oxycodone free base. The
obtained organic layer is dried over sodium sulfate and methylene
chloride is evaporated using rotary evaporator. The obtained
oxycodone free base is purified by crystallization.
EXAMPLE 2
Preparation of Drug Containing Microparticles
TABLE-US-00001 [0069] TABLE 1 Compositions Composition Composition
Composition Composition of of of of Formulation Formulation
Formulation Formulation Ingredient A B C D Oxycodone 5 g 5 g 10 g 5
g Base Myristic Acid -- -- 50 g 30 g Stearic Acid 34 g 34 g -- --
Yellow 10 g -- 10 g 10 g Beeswax Carnauba wax 5 g 10 g 20 g 10
g
Procedure:
[0070] 1. Fatty acid (myristic or stearic acid) was melted in an
erlenmeyer flask in a silicone oil bath at 100.degree. C. Note the
composition was subjected to stirring and was kept under an argon
blanket for this and all subsequent steps. 2. Oxycodone base was
introduced into the molten fatty acid and the melt was stirred
until all oxycodone base dissolved and a clear liquid was formed.
3. Yellow beeswax was added and melted under constant stirring. 4.
Carnauba wax was added and melted under constant stirring. 5. The
resulting homogeneous molten solution was poured onto aluminum foil
and allowed to solidify at room temperature. 6. The bulk wax
obtained was combined with dry ice and subjected to size reduction
in a mortar and pestle. 7. The dry ice was allowed to dissipate and
the particles were sieved to obtain various size ranges. Particles
20-40 mesh in size (400-841 micron) were subjected to testing.
EXAMPLE 3
Release of Drug from Crushed Microparticles
[0071] In vitro testing was conducted in order to assess the
influence of crushing of the microparticles produced in Example 2
on the release in simulated stomach conditions. A currently
marketed sustained release formulation of oxycodone,
OxyContin.RTM., was also subjected to crushing and dissolution for
comparison purposes.
[0072] Microparticles (Formulations A, B, C or D, all 20-40 mesh in
starting particle size) or tablets were crushed using a glass
mortar & pestle. The resulting crushed material was placed in a
dissolution vessel equipped with paddles (USP Apparatus II). 900 mL
of 0.1N HCl pre-warmed to 37.degree. C. was added to the vessels
and stirring was conducted for 15 minutes. After 15 minutes the
amount of oxycodone released was determined. See Table 2.
TABLE-US-00002 TABLE 2 Oxycontin Formulations % Released in 15
minutes in 0.1N HCl Sample (n = 3) Oxycontin .RTM. 95.6 +/- 2.7 (40
mg Tablet) Formulation A 31.6 +/- 2.6 (microparticles containing 40
mg oxycodone HCl equivalent) Formulation B 19.7 +/- 1.4
(microparticles containing 40 mg oxycodone HCl equivalent)
Formulation C 14.8 +/- 1.1 (microparticles containing 20 mg
oxycodone HCl equivalent) Formulation D 18.2 +/- 1.6
(microparticles containing 20 mg oxycodone HCl equivalent)
[0073] As illustrated in the table above, the microparticle
compositions of Example 2 release only a fraction of the total drug
load in simulated stomach conditions when crushed. In contrast, a
currently marketed sustained release composition, OxyContin.RTM.,
releases approximately 96% of the drug load when crushed and
exposed to identical conditions.
EXAMPLE 4
Preparation of Coated Drug Containing Microparticles
[0074] The drug-containing particles from Example 2 are spray
coated with cellulose acetate phalate.
EXAMPLE 5
Preparation of Capsules for Oral Administration
[0075] The drug containing microparticles from Example 2 and/or the
coated microparticles from Example 3 are blended with a lubricant
and incorporated into standard gelatin capsules.
[0076] Modifications and variations of the present invention will
be obvious to those skilled in the art.
* * * * *