WO2005044238A1

WO2005044238A1 - Modified release solid dosage form of amphetamine salts

Info

Publication number: WO2005044238A1
Application number: PCT/IB2004/003621
Authority: WO
Inventors: Pratik Kumar; Girish Kumar Jain; Naresh Talwar; Ashok Kumar Rampal
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2003-11-07
Filing date: 2004-11-05
Publication date: 2005-05-19
Anticipated expiration: 2006-05-07

Abstract

The technical field of the present invention relates to solid dosage forms of amphetamine salt that include a plurality of modified release units; and processes of preparation thereof. Each modified release unit includes an inert core, a first amphetamine salt layer, a modified release polymer layer, and a second amphetamine salt layer.

Description

MODIFIED RELEASE SOLID DOSAGE FORMS OF AMPHETAMINE SALTS Field of Invention The technical field of the present invention relates to solid dosage forms of amphetamine salt or salts that include a plurality of modified release units; and processes of preparation thereof. Background of the Invention Amphetamine salts are a useful class of central nervous system stimulating agents. They are non-catecholamine, sympathomimetic amines with central nervous system (CNS) stimulant activity. In addition to CNS activity, they may have peripheral actions that include elevations of systolic and diastolic blood pressure, weak bronchodilation, and respiratory stimulant action. Amphetamine salts are effective in treating narcolepsy, attention deficit disorder and a few types of obesity. Conventional immediate release tablets of amphetamine salts need to be administered 2-4 times a day, based on the condition of the patient. To avoid the inconvenience of multiple dosing, modified release approaches have been designed that reduce the frequency of administration. Further, to achieve quick onset of action some portion of the dose needs to be administered immediately. Hence, dosage forms comprising both modified release and an immediate release portions may be helpful in this regard. In the prior art, modified release and immediate release of drug from the same dosage form has been attempted by combining more than one type of units having different release profiles. For example, U.S. Patent No. 6,228,398 discloses a multiparticulate modified release composition that includes a combination of immediate release particles and modified release particles. U.S. Patent Nos. 5,837,284 and 6,322,819 disclose modified release solid dosage forms of amphetamine salts that include a combination of immediate release and modified release particles. In the above approaches the units having different release profiles should be mixed homogenously as improper mixing may cause batch-to-batch variations in the release profiles. Further, preparation of separate units having immediate and modified release profiles may be a lengthy and cumbersome process. Hence, there exists a need for better approaches, which could be easily manufactured, and would guarantee accurate dosing in correct proportions from both the components. We have now discovered that this can be achieved by formulating different release components in the same unit. Summary of the Invention In one general aspect there is provided a solid dosage form that contains a plurality of modified release units. Each modified release unit includes an inert core, a first amphetamine salt layer, a modified release polymer layer, and a second amphetamine salt layer. Embodiments of the solid dosage form may contain one or more of the following features. For example, the amphetamine salts may be selected from the group consisting of amphetamine, methylphenidate and their pharmaceutically acceptable salts. The amphetamine salts may be a mixture of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulphate and amphetamine sulphate. The amphetamine salt may be methylphenidate hydrochloride. The inert core may be one or more of a pharmaceutically acceptable inert water soluble, insoluble or swellable material. The water soluble material may be a sugar comprising one or more of glucose, mannitol, lactose, xylitol, dextrose, and sucrose. The water insoluble material may be one or more of sand, silicon dioxide, glass, microcrystalline cellulose and plastic. The water swellable material may be hydroxypropyl methylcellulose. The inert core may be one or more of sugar spheres, non pareil seeds, and celpheres. In particular, the inert core may be non pareil seeds. The modified release polymer layer may be one or more pH-independent polymers selected from the group comprising cellulose polymers comprising one or more of ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymefhylcellulose, hydroxymethylcellulose, hydroxyefhylcellulose, and cellulose acetate; waxes comprising polyethylene glycols; and methacrylic acid copolymers comprising one or more of copolymers of acrylate and methacrylates with quartemary ammonium groups, and copolymers of acrylate and methacrylates with quartemary ammonium groups in combination with sodium carboxymefhylcellulose. In particular, the modified release polymer may be ethylcellulose and/or a copolymer of acrylate and methacrylates with quartemary ammonium group. The amphetamine salt may be released from the dosage form in a pulsatile manner. A first pulse of the amphetamine salt may be released immediately from the immediate release layer, and a second pulse of amphetamine salt may be released from the modified release amphetamine salt layer after a lag time of about 2 to about 8 hours. The second pulse of amphetamine salt may be released over about 30 minutes to about 3 hours. The solid dosage form may be a tablet or a capsule. The solid dosage form may further include one or more pharmaceutically acceptable inert excipients. The one or more pharmaceutically acceptable inert excipients may be selected from the group consisting of binders, diluents, disintegrants, surfactants, plasticizers, lubricants/glidants, coloring agents, and flavoring agents. In another general aspect there is provided a process of making a solid dosage form. The process includes coating an inert core with a first layer, the first layer including a first amphetamine salt; coating the first layer with a modified release polymer layer to form a second layer; and coating the second layer with a third layer, the third layer including a second amphetamine salt. Embodiments of the process may include one or more of the following features or those described above. For example, the layers may be applied as a solution/dispersion of coating ingredients. The solution/dispersion may be prepared in solvent selected from the group consisting of methyl ene chloride, isopropyl alcohol, acetone, methanol, ethanol, and water. In particular, the solvent may be water. The coating layers may be applied using a hot melt technique. In another general aspect there is provided a method for administering amphetamine salts to a mammal in need thereof. The method includes administering a solid dosage form of one or more amphetamine salts, the solid dosage form including a plurality of modified release units. Each modified release unit includes an inert core; a first amphetamine salt layer; a modified release polymer layer; and a second amphetamine salt layer. Embodiments of the method may include one or more of the features described above. The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims. Detailed Description of the Invention The term "modified release" as used herein includes all types of modified release profiles such as controlled release, sustained release, delayed release, pulsatile release, timed release, and the like. The term "solid dosage form" as used herein includes dosage forms for oral administration such as tablet, capsule, and the like. The second amphetamine salt layer provides immediate release, whereas the first amphetamine salt layer that is enclosed by the modified release polymer layer provides the modified release doses of amphetamine salt. The dosage form of the present invention has both modified release and immediate release portions of amphetamine salt on the same inert core, which assures accurate dosing. When administered, individual modified release units of the solid dosage form will disperse rapidly into gastric fluid. The dosage form further provides all the advantages of multiple unit systems such as administration of divided doses, decreased chances of dose dumping and drug release independent of variations in gastric emptying. Above all, the dosage form may be prepared in single equipment in a continuous process, making the dosage form preparation economical and relatively fast. The total dose may be distributed in the immediate release layer and modified release layers in different ratios, depending upon the desired drug release profiles. On oral administration, amphetamine salt from the immediate release layer will be released immediately, much as it would be released from a conventional immediate release dosage form. This immediate release of drug will be followed with release of the drug from the modified release layer. In particular, amphetamine salt(s) from the immediate release layer is released within about 30 minutes after administration. This immediate release is followed by a pulsatile release from the modified release layer after a lag time of about 2 to about 8 hours, with the release continuing over a period of about 30 minutes to about 3 hours. The term "amphetamine salt" as used herein includes amphetamine salt and salts, amphetamine base, all chemical and chiral derivatives and salts thereof such as dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulphate and amphetamine sulphate; methylphenidate, all chemical and chiral derivatives and salts thereof; phenylpropanolamme and salts thereof; and all other compounds indicated for the treatment of attention deficit hyperactivity disorder. Examples of inert cores include pharmaceutically acceptable inert cores available commercially or prepared from inert material by process of extrusion-spheronization, granulation, and the like. Specific examples of commercially available inert cores include sugar spheres, non-pareil seeds, celpheres, and the like. Alternatively, inert cores may be prepared from pharmaceutically acceptable inert soluble, insoluble or swellable material, with or without other pharmaceutically acceptable inert excipients. Specific examples of insoluble inert material include sand (silicon dioxide), glass, microcrystalline cellulose and plastic (polystyrene). On the other hand, soluble inert material includes sugars selected from glucose, mannitol, lactose, xylitol, dextrose, sucrose and the like. Swellable inert material includes hydroxypropyl methylcellulose, and the like. The modified release polymer layer comprises one or more pH independent polymers with or without other pharmaceutically acceptable inert excipients. Examples of pH independent polymers include cellulose polymers such as ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymefhylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate; waxes such as polyethylene glycols; methacrylic acid copolymers such as copolymer of acrylate and methacrylates with quartemary ammonium group, and copolymer of acrylate and methacrylates with quartemary ammonium group in combination with sodium carboxymefhylcellulose; and the like. The term "pharmaceutically acceptable inert excipients" as used herein includes all physiologically inert excipients used in the pharmaceutical art of dispensing. Examples include binders, diluents, disintegrants, surfactants, plasticizers, lubricants/glidants, coloring agents, flavoring agents, and the like. Specific examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like. Specific examples of diluents include calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like. Surfactants include both non-ionic and ionic (i.e., cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms. These include polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterifϊcation products, for example polyethylene glycol - 6 com oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides for example glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether, polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and the like. Specific examples of disintegrants include low-substituted hydroxypropylcellulose, sodium starch glycollate, carboxymefhyl cellulose, calcium carboxymefhyl cellulose, sodium carboxymefhyl cellulose, croscarmellose sodium A-type (Ac-di-sol), starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, and the like. Specific examples of lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like. Specific examples of plasticizers include polyethylene glycol, polysorbate 80, glyceryl monostearate, triethyl citrate, diethyl phthalate, dibutyl sebacate, and the like. Coloring agents and flavoring agents include any FDA approved colors and flavors for oral use. The modified release solid dosage form of amphetamine salts may be prepared by processes known in the prior art, e.g., by comminuting, mixing, granulation, sizing, filling, molding, spraying, immersing, coating, compressing, etc. In one of the embodiments, the solid dosage form of amphetamine salts may be prepared by a process comprising the steps of a. Loading inert cores in a coating equipment, b. Spraying a solution/dispersion of amphetamine salts and one or more pharmaceutically acceptable inert excipients to form a first amphetamine salts layer, c. Spraying a solution/dispersion of pH independent modified release polymer and pharmaceutically acceptable inert excipients to form a modified release polymer layer, d. Spraying a solution/dispersion of amphetamine salt and one or more pharmaceutically acceptable inert excipients to form a second amphetamine salt layer, e. Optionally blending the modified release units formed above with lubricant/glidant, and f. Filling into a suitable sized capsule. Alternatively, the modified release units may be blended with disintegrant and optionally with other pharmaceutically acceptable inert excipient and compressed into tablets. The coating layers over the inert cores may be applied as solution dispersion of coating ingredients using any conventional technique known in the prior art such as spray coating in a conventional coating pan or fluidized bed processor, dip coating, and the like. Alternatively the layers over the inert cores may also be applied using a hot melt technique. Examples of solvents used for preparing a solution/dispersion of the coating ingredients include methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water, and the like. Alternatively, the modified release units may further comprise one or more suitable functional/non-functional layers over the inert core, in-between any two layers, and/or over the immediate release layer. The invention is further illustrated by the following examples, which are for illustrative purposes and should not be construed as limiting the scope of the invention in any way.

Example Table 1. Coatin solution of the am hetamine salt la er

Procedure: 1. Non pareil seeds (cores) (# 30/35 mesh) were loaded in a bottom spray Fluid bed processor. 2. Amphetamine salts were dissolved in water to form a solution (as per Table 1). 3. The solution of step 2 was sprayed on the non pareil seeds of step 1 and dried to form a first amphetamine salt layer, equivalent to 15 mg amphetamine salts. 4. Commercially available ethylcellulose (Surelease®) was dispersed in water to form a 25%w/w solution and sprayed on the cores of step 3 and dried up to a weight gain of about 10%, to form a modified release layer. 5. The solution of step 2 was sprayed on the cores of step 4 and dried to form a second amphetamine salt layer, equivalent to 15 mg amphetamine salts. 6. The cores (equivalent to 30 mg amphetamine salts) of step 5 were filled into hard gelatin capsules. While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text and claims can be made without departing from the spirit and scope of the invention. For example, methylphenidate hydrochloride may be dissolved in water to form a solution which may be coated over non pareil seeds as in the above example to provide modified release solid dosage forms. Accordingly, it is not intended that the invention be limited, except as by the appended claims.

Claims

We Claim: 1. A solid dosage form comprising a plurality of modified release units, each modified release unit comprising: a. an inert core; b. a first amphetamine salt layer; c. a modified release polymer layer; and d. a second amphetamine salt layer.

2. The solid dosage form according to claim 1 wherein the amphetamine salts are selected from the group consisting of amphetamine, methylphenidate and their pharmaceutically acceptable salts.

3. The solid dosage form according to claim 2 wherein the amphetamine salts are a mixture of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulphate and amphetamine sulphate.

4. The solid dosage form according to claim 2 wherein the amphetamine salt comprises methylphenidate hydrochloride.

5. The solid dosage form according to claim 1 wherein the inert core comprises one or more of a pharmaceutically acceptable inert water soluble, insoluble or swellable material.

6. The solid dosage form according to claim 5 wherein the water soluble material is a sugar comprising one or more of glucose, mannitol, lactose, xylitol, dextrose, and sucrose.

7. The solid dosage form according to claim 5 wherein the water insoluble material comprises one or more of sand, silicon dioxide, glass, microcrystalline cellulose and plastic.

8. The solid dosage form according to claim 5 wherein the water swellable material comprises hydroxypropyl methylcellulose.

9. The solid dosage form according to claim 1 wherein inert core comprises one or more of sugar spheres, non pareil seeds, and celpheres.

10. The solid dosage form according to claim 9 wherein the inert core comprises non pareil seeds.

11. The solid dosage form according to claim 1 wherein the modified release polymer layer comprises one or more pH-independent polymers selected from cellulose polymers comprising one or more of ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymefhylcellulose, hydroxymethylcellulose, hydroxyefhylcellulose, and cellulose acetate; waxes comprising polyethylene glycols; and methacrylic acid copolymers comprising one or more of copolymers of acrylate and methacrylates with quartemary ammonium groups, and copolymers of acrylate and methacrylates with quartemary ammonium groups in combination with sodium carboxymefhylcellulose.

12. The solid dosage form according to claim 1 1 wherein the modified release polymer comprises ethylcellulose.

13. The solid dosage form according to claim 11 wherein modified release polymer comprises a copolymer of acrylate and methacrylates with quartemary ammonium group.

14. The solid dosage form according to claim 1 wherein the amphetamine salt is released from the dosage form in a pulsatile manner.

15. The solid dosage form according to claim 14 wherein a first pulse of amphetamine salt is released immediately from the immediate release layer, and a second pulse of amphetamine salt is released from the modified release amphetamine salt layer after a lag time of about 2 to about 8 hours.

16. The solid dosage form according to claim 15 wherein the second pulse of amphetamine salt is released over about 30 minutes to about 3 hours.

17. The solid dosage form according to claim 1 wherein the solid dosage form is a tablet.

18. The solid dosage form according to claim 1 wherein the solid dosage form is a capsule.

19. The solid dosage form according to claim 1 wherein the dosage form further comprises one or more pharmaceutically acceptable inert excipients.

20. The solid dosage form according to claim 19 wherein the one or more pharmaceutically acceptable inert excipients are selected from the group consisting of binders, diluents, disintegrants, surfactants, plasticizers, lubricants/glidants, coloring agents, and flavoring agents.

21. A process of making a solid dosage form, the process comprising: coating an inert core with a first layer, the first layer comprising a first amphetamine salt; coating the first layer with a modified release polymer layer to form a second layer; and coating the second layer with a third layer, the third layer comprising a second amphetamine salt.

22. The process according to claim 21 wherein the layers are applied as a solution/ dispersion of coating ingredients.

23. The process according to claim 22 wherein the solution/dispersion is prepared in solvent selected from the group consisting of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, and water.

24. The process according to claim 23 wherein the solvent comprises water.

25. The process according to claim 21 wherein the coating layers are applied using a hot melt technique.

26. A method for administering amphetamine salts to a mammal in need thereof, the method comprising administering a solid dosage form of one or more amphetamine salts, the solid dosage form comprising a plurality of modified release units, each modified release unit comprising: an inert core; a first amphetamine salt layer; a modified release polymer layer; and a second amphetamine salt layer.