Oxycodone immediate release tablets



Patent WO2013077851A1

01/24/2017
05:24 | Olivia Holiday
Oxycodone immediate release tablets
Patent WO2013077851A1

The tablet of claim 3 wherein the drug is oxycodone or a.. Immediate release oxycodone hydrochloride tablets with the following composition.

a) a therapeutically effective amount of a drug that is subject to abuse, preferably comprising about 0.5 weight percent to about 75 weight percent of the total tablet weight, preferably about 1 weight percent to about 50 weight percent of the total tablet weight; b) a gelling agent comprising about 1 weight percent to about 20 weight percent of the total tablet weight, preferably about 3 weight percent to about 15 weight percent of the total tablet weight; c) an effervescent agent comprising about 1 weight percent to about 20 weight percent of the total tablet weight, preferably about 2 weight percent to about 10 weight percent of the total tablet weight; and.

For example, typical therapeutic amounts of hydromorphone range from about 4 mg to about 64 mg of the hydrochloride salt, typical therapeutic amounts of morphine range from about 5 mg to about 800 mg and typical therapeutic amount of oxycodone range from about 5 mg to abut 400 mg for the hydrochloride salt. The therapeutic amounts of the drugs used in the present invention are known in the art and can be found in the literature such as Goodman & Gillman's, The Pharmacological Basis of Therapeutics, 9th ed. pages 219-222, 361-396, 521-535.

iv) optionally about 1 to about 10 weight percent of a second nasal irritant other than the effervescent agent; and.

The amount of disintegrant that may be employed in the tablets of the present invention is generally about 0.5 weight percent to about 10 weight percent based upon the total weight of the tablet and preferably about 1 weight percent to about 5 weight percent based upon the total weight of the tablet. foregoing.

(2006). A more detailed description of the pharmaceutical excipients that may also be included in the tablets of the present invention can be found in The Handbook of Pharmaceutical Excipients, 5th ed. Embodiments of tablets prepared in accordance with the present invention may further comprise conventional pharmaceutical excipients selected from the group consisting of fillers, binders, lubricants, glidants, disintegrants, coloring agents and mixtures thereof.

4: 1. The effervescent agent employed in the present invention is a material or.

The amount of lubricant that may be employed in the tablets of the present invention is generally about 0.05 weight percent to about 15 weight percent based upon the total weight of the tablet, preferably about 0.1 weight percent to about 10 weight percent based upon the total weight of the tablet and most preferably about 0.5 weight percent to about 5 weight percent based upon the total weight of the tablet. Examples of lubricants that may be used in the present invention include, but are not limited to talc, glyceryl monostearates, calcium stearate, magnesium stearate, stearic acid, glyceryl behenate, polyethylene glycol, poloxamer and combinations of the foregoing.

The present invention is an immediate release tablet with abuse deterrent characteristics and a method for making the immediate release tablet. The tablet comprises:.

i) a therapeutically effective amount of a drug that is subject to abuse;

Embodiments of tablets prepared in accordance with the present invention may further comprise conventional pharmaceutical processing excipients selected from the group consisting of fillers, binders, lubricants, glidants, disintegrants, coloring agents and mixtures thereof.

A further embodiment of the present invention comprises a method for preparing an immediate release abuse deterrent tablet that comprises the steps of: a) dry mixing:. One embodiment of the present invention will comprise a second nasal irritant that is different from the effervescent agent. In this embodiment the second nasal irritant may comprise about 0.5 to about 10 weight percent of tablet.

b) compressing the dry mixture into tablets that release substantially all of the drug in about 15 to about 60 minutes when placed into 500 ml of an aqueous media. BRIEF DESCRIPTION OF THE DRAWINGS.

FIELD OF THE INVENTION.

It is a further object of the present invention to provide a method for preparing immediate release tablets, preferably immediate release opioid tablets, which are subject to less abuse.

Figure 1 is the dissolution profile of the 5 mg tablet of Example 3.

DETAILED DESCRIPTION OF THE INVENTION.

Time Preferred % Release Most Preferred % Release.

Figure 2 is the dissolution profile of the 7.5 mg tablet of Example 3.

The solid oral dosage forms of the present invention contain an effervescent agent and are designed to release substantially all of the drug in about 15 to about 60 minutes. The present invention relates to the field of solid oral dosage forms and in particular solid immediate release tablets that contain a drug which is subject to abuse.

45 min 60-100% 75-100%

The amount of glidant that may be employed in the tablets of the present invention is generally about 0.1 weight percent to about 7.5 weight percent based upon the total weight of the tablet and preferably about 0.5 weight percent to about 5 weight percent based upon the total weight of the tablet. Examples of disintegrants that may be used in the present invention include, but are not limited to corn starch, croscarmellose sodium, crospovidone (polyplasdone XL- 10). Examples of glidants that may be used in the present invention include, but are not limited to colloidal silicon dioxide (Cab-O-Sil) and Quso (also known as Phila Quartz).

It is an object of the present invention to provide an improved abuse deterrent solid oral dosage form that is safe, effective and easy to manufacture.

2009/0081290 describe crush resistant opioid dosage forms that contain polyethylene oxide. United States Published Patent Application No. Another method described in the art to deter illicit use of pharmaceutical products is to include aversive agents such as irritating agents for the nasal and/or pharyngeal tracts, antagonist agents for the drug that is being abused, bittering agents, visual modifying agents, emetic agents and viscosity increasing agents. Patent Nos. 7,682,633 and 7,658,939. 2010/0015223 describes hard opioid matrix tablets that release the opioid drug over extended periods of time and that are difficult to crush. 7,776,314 and European Patent. Examples of abuse deterrent dosage forms employing viscosity increasing agents are described in U.S. Patent No. Examples of abuse deterrent dosage forms employing irritating agents and/or emetic agents are described in U.S. 7,510,726. Patent No. Examples of abuse deterrent dosage forms employing antagonist agents are described in U.S.

It is a further object of the present invention to provide an immediate release tablet which is subject to less abuse, preferably less intranasal abuse.

Figure 5 is the dissolution profile of the 7.5 mg tablet of Example 5.

v) optionally conventional pharmaceutical processing excipients selected from the group consisting of fillers, binders, lubricants, glidants, disintegrants, coloring agents and mixtures thereof; and.

DISSOLUTION of the United States Pharmacopeia.

d) optionally a second nasal irritant other than the effervescent agent comprising about 0.5 weight percent to about 10 weight percent of the total tablet weight, preferably about 1 weight percent to about 5 weight percent of the total tablet weight.

The alkaline source should release oxygen or carbon dioxide gas when reacting with the acid source. One embodiment of the alkaline source is a material that will release carbon dioxide when reacted with the acid source such as carbonates and. Acid salts such as sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acid sulfite and metal salts of citric acid, tartaric acid, malic acid, maleic acid, lactic acid, glycolic acid, ascorbic acid, fumaric acid, adipic acid and succinic acid, such as sodium citrate or sodium tartrate, may also be employed as the acid source of the effervescent agent. The acid source should be an acid that is safe for human consumption and generally includes organic acids such as citric acid, tartaric acid, malic acid, maleic acid, lactic acid, glycolic acid, ascorbic acid, fumaric acid, adipic acid, succinic acid and combinations thereof. The gas generating reaction is typically the result of a reaction between an acid source and an alkaline source. combination of materials that evolve gas by means of a chemical reaction that takes place upon the exposure of the tablet to an aqueous media such as saliva, gastric fluid or intestinal fluid.

6,419,954, 4,915,949, 4,327,725, 4,207,893 and in Handbook of Common Polymers, by Scott and Roff, published by Cleveland Rubber Company, Cleveland, OH. Nos. Representative polymers possessing gelling properties are described in U.S. Nos. Other gelling agents useful in the present invention include pectin having a molecular weight ranging from 30,000 to 300,000; polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar; Carbopol, an acrylic acid polymer, a carboxyvinyl polymer, sometimes referred to as carboxypolymethylene, a polymer of acrylic acid cross-linked with a polyallyl ether of sucrose, as described in U.S. poly(hydroxyalkylmethacrylate) having a molecular weight of from 5,000 to 5,000,000; poly(vinylpyrrolidone) having a molecular weight of from 100,000 to 3,000,000; anionic and cationic hydrogels; poly(electrolyte) complexes; poly(vinylalcohol) having a low acetate residual; a swellable mixture of agar and carboxymethyl cellulose; a swellable composition comprising methyl cellulose mixed with a sparingly cross-linked agar; a polyether having a molecular weight of from 10,000 to 6,000,000; water swellable copolymer produced by a dispersion of finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, or isobutylene; water swellable polymer of N-vinyl lactams; and the like. Pat. Patent. 2,798,053 and 2,909,462 and available as Carbopol 934, 940 and 941, and its salt derivatives; polyacrylamides; water- swellable indene maleic anhydride polymers; Good-rite polyacrylic acid having a molecular weight of 80,000 to 200,000; Polyox polyethylene oxide polymers having a molecular weight of 100,000 to 7,000,000; starch graft copolymers; Aqua-Keep acrylate polymers with water absorbability of about 400 times its original weight; diesters of polyglucan; a mixture of cross-linked polyvinyl alcohol and poly( -vinyl-2-pyrrolidone); poly(ethylene glycol) having a molecular weight of 4,000 to 100,000.

30 min 20-75% 30-70%

sodium starch glycolate (EXPLOTAB or PRIMOJEL) or any combination of the.

Patent No. Application No. 6,514,531, and examples of abuse deterrent dosage forms employing bittering agents are provided in U.S. 7,141,250. 0 661 045. Patent No. Although the art contains many examples of abuse deterrent dosage forms there is a constant need to improve the deterrents to abuse and to prepare a safe and effective solid dosage form in a simple, easy and cost effective manner. Examples of abuse deterrent dosage forms employing visual modifying agents are described U.S.

dihydrocodeine, dihydromorphine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone or pharmaceutically acceptable salts therefore.

BACKGROUND OF THE INVENTION.

b) about 1 to about 20 weight percent of a gelling agent; and.

c) about 1 to about 20 weight percent of an effervescent agent wherein the tablet releases substantially all of the drug in about 15 to about 60 minutes when placed into 500 ml of an aqueous media. It is believed that the gelling agent will make extraction of the drug substance from the crushed tablet difficult and the effervescent agent will act as a nasal irritant that will deter inhalation.

The binders also may exhibit a low molecular weight and/or low viscosity when measured in a 2% aqueous solution. The low molecular weight binders typically are polymers with a molecular weight of less than 50,000, preferably less than 30,000, and preferably less than 10,000. The low viscosity binders typically have a viscosity of about 50 mPa-s or lower, preferably about 25 mPa-s or lower and most preferably 15 mPa-s or lower. Examples of binders that may be employed in the present invention include, but are not limited to acacia, alginic acid, sodium carboxymethylcellulose sodium, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, starch, polyvinyl alcohol, polyethylene oxide, polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose and any combination of the foregoing. The binders may be water soluble materials. The amount of binder that may be employed in the tablets of the present invention is generally about 1 weight percent to about 25 weight percent based upon the total weight of the tablet and preferably about 3 weight percent to about 15 weight percent based upon the total weight of the tablet.

The release can be measured according to the procedures described in section <71 1>. The tablets of the present invention should release substantially all of the drug in about 15 to about 60 minutes when placed into 500 ml of an aqueous media. The tablets should release the drug in a pH independent manner meaning the drug should be released from the tablet at substantially the same rate regardless of the pH of the aqueous media.

30 min 40-90% 50-80%

Figure 3 is the dissolution profile of the 5 mg tablet of Example 4.

iii) about 1 to about 20 weight percent of an effervescent agent;

IMMEDIATE RELEASE ABUSE DETERRENT TABLET.

Figure 7 is the dissolution profile of the 7.5 mg tablet of Example 6.

The amount of filler that may be employed in the tablets of the present invention is generally about 5 weight percent to about 75 weight percent based upon the total weight of the tablet and preferably about 10 weight percent to about 50 weight percent based upon the total weight of the tablet. Examples of fillers that may be employed in the present invention include, but are not limited to lactose, starch, dextrose, sucrose, fructose, maltose, mannitol, sorbitol, kaolin, microcrystalline cellulose, powdered cellulose, dextrates, calcium sulfate, calcium phosphate, dicalcium phosphate, lactitol or any combination of the foregoing.

For example United States Published Patent Application Nos. 2005/0031546 and. Due to the increased illicit use of pharmaceutical products there has been an effort to design solid oral dosage forms that will hopefully deter or prevent their misuse and abuse.

The polymer can be of plant, animal or synthetic origin. The cross-links can be covalent or ionic bonds with the polymer possessing the ability to swell in the presence of fluid, and when cross-linked it will not be dissolved in the fluid. The gelling agent that may be employed in the tablets of the present invention is a material that exhibits the ability to retain a significant fraction of imbibed fluid in the molecular structure. The swelling or expansion of the gelling agent usually exhibits a 2 to 50 fold volume increase from the dry state. The gelling agents are materials that can swell or expand when in contact with an aqueous media such as gastric or intestinal fluid to a very high degree. Polymeric materials useful for the present purpose include. Examples of gelling agents that may be used in the present invention include swellable polymers, also known as osmopolymers or hydrogels. The swellable polymer can be non-cross-linked or lightly cross-linked.

Embodiments of the present invention may also further comprise additional aversive agents such as a second or additional irritating agent for the nasal and/or pharyngeal tracts, antagonist agents for the drug that is being abused, bittering agents, visual modifying agents, emetic agents and combinations of the forgoing.

Time Preferred % Release Most Preferred % Release.

Although pharmaceutical dosage forms are designed to be safe and effective in the treatment of various afflictions, they are sometimes misused and subject to illicit use and/or abuse by individuals. Some of the more commonly misused pharmaceutical dosage forms contain opioids, sedatives, stimulants and hypnotics. One of the more common illicit practices is to obtain solid dosage forms such as tablets or capsules and manipulate the solid dosage form, typically by crushing the solid dosage form, and to extract the drug to allow the drug to be administered by inhalation or injection.

Figure 4 is the dissolution profile of the 7.5 mg tablet of Example 4.

ii) about 1 to about 20 weight percent of a gelling agent;

polyhydroalkylcellulose having a molecular weight greater than 50,000.

45 min 70-100% 80-100% Examples of drugs that are subject to abuse and that may be used in the present invention include opioids, tranquilizers, sedatives and stimulants. Examples of such drugs can be found on pages of Remington, The Science and Practice of Pharmacy, 21st ed. (2005). Specific examples of the drugs that may be used in the present invention include alfentanil, alimemazine, alprazolam, amphetamine, buprenorphine, butorphanol, clonazepam, codeine, cyclobenazprine, diazepam, dihydrocodeine, dihydromorphine, dronabinol, estazolam, ezopiclone, fentanyl, flurazepam, hydrocodone, hydromorphone, lorazepam, methobarbital, methylphenidate, methadone, morphine, oxycodone, oxymorphone, phenobarbital, secobarbital, tempazepam, tramadol, triazolam, zaleplon, zopiclone, Zolpidem or pharmaceutically acceptable salts thereof. Specific embodiments of the present invention comprise opioids selected from the group consisting of buprenorphine, codeine.

Figure 6 is the dissolution profile of the 5 mg tablet of Example 6.

The ratio of the first, or lower, molecular weight polyethylene oxide to the second, or higher, molecular weight polyethylene oxide is about 1 :5 to about 5 : 1 preferably about 1 :4 to about. An alternative embodiment of the present invention employs a combination of two or more gelling agents preferably selected from the group consisting of polyethylene oxide, hydroxypropyl cellulose with a molecular weight of about 50,000 to about 125,000, hydroxypropyl methylcellulose with a 2% (w/v) aqueous viscosity at 20°C between about 50 mPa-s and about 100,000 mPa-s, and polyvinylpyrrolidone with a molecular weight between 400,000 to about 3,000,000. One embodiment of the present invention employs a mixture of at least two different types of polyethylene oxides wherein the first polyethylene oxides has an approximate molecular weight between 500,000 and 1,000,000 and the second polyethylene oxide has an approximate molecular weight between 2,000,000 and 5,000,000.

SUMMARY OF THE INVENTION.

These and other objectives are achieved by a solid pharmaceutical tablet comprising: a) a therapeutically effective amount of a drug that is subject to abuse;

Another embodiment of the alkaline source is a material that will release oxygen. Examples of the carbonates and bicarbonate that may be used in the present invention include sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate, sodium sequicarbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate, calcium carbonate, calcium bicarbonate and mixtures of the foregoing. Examples of compounds that will release oxygen are anhydrous sodium perborate, effervescent perborate, sodium perborate monohydrate, sodium precarboante and mixtures thereof. bicarbonates.

One embodiment of the present invention will release the drug with the following profile:

The polyethylene oxide should have an approximate molecular weight of about 100,000 to 7,000,000, preferably between about 500,000 and about 5,000,000 and most preferably about 900,000 to about 5,000,000. One embodiment of the present invention employs polyethylene oxide as the gelling agent.

Another embodiment of the present invention will release the drug with the following profile: