Claims:We Claim:

1. A modified release pharmaceutical composition of Memantine HCl extended-release (ER) and donepezil HCl immediate-release (IR) comprising:
a seal coated core;
a first drug layer applied to the seal coated core comprising Memantine HCl extended-release (ER) with at least one pharmaceutically acceptable excipient(s) to provide a drug coated pellet;
a sub coat applied on the drug coated pellet using one or more rate controlling polymers to provide a sub-coated pellet;
a polymer coat applied on the sub-coated pellet using the one or more rate controlling polymers to provide a polymer coated pellet;
a second drug layer of Memantine HCl extended-release (ER) with at least one pharmaceutically acceptable excipient(s) applied on the polymer coated pellet to provide an intermediate 1;
a second seal coat applied on the intermediate 1 to provide a seal coated intermediate 1; and
at least one coat of Donepezil HCl immediate-release (IR) drug layer with at least one pharmaceutically acceptable excipient(s) coated on the seal coated intermediate 1 to provide the modified release pharmaceutical composition of Memantine HCl extended-release (ER) and Donepezil HCl immediate-release (IR).

2. The modified release pharmaceutical composition as claimed in claim 1, wherein the core comprises water soluble/insoluble inert cores coated with memantine extended-release (ER) or salts thereof.

3. The modified release pharmaceutical composition as claimed in claim 1, wherein the rate controlling polymer comprises one or more of ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides, methyl acrylates, alkyl phthalates, cellulose acetate phthalate, polyethylene oxides, and polyethylene glycols.

5. The modified release pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable binder comprises one or more of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, gum arabic, polymethacrylates, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, carrageenan, polyethylene oxide, waxes, pullulan, agar, tragacanth, veegum, pregelatinized starch, sodium alginate, gums and sugars.

6. The modified release pharmaceutical composition as claimed in claim 1, wherein the Memantine HCl extended-release (ER) comprise more than 2% by weight of one or more pharmaceutically acceptable binders.

7. The modified release pharmaceutical composition as claimed in claim 1, wherein the Donepezil HCl immediate-release (IR) comprise more than 1% by weight of one or more pharmaceutically acceptable binders.

8. The modified release pharmaceutical composition as claimed in claim 1 in the form of a tablet, a capsule, granules, pellets, caplets, minitablets, a capsule filled with minitablets and/or pellets, a multi-layer tablet, granules for suspension, or granules filled in a sachet.

9. The modified release pharmaceutical composition as claimed in claim 1, wherein the composition comprises about 4%-15% by weight of the immediate release component, and about 12% by weight of the sustained release components.

10. A process for the preparation of a modified release pharmaceutical composition, the process comprising:

(a) providing a plurality of Memantine HCl extended-release (ER) with at least one pharmaceutically acceptable excipient(s);

(b) providing a plurality of Donepezil HCl immediate-release (IR) drug layer with at least one pharmaceutically acceptable excipient(s); and

(c) coating the of Donepezil HCl immediate-release (IR) drug layer with at least one pharmaceutically acceptable excipient(s) over the Memantine HCl extended-release (ER) with at least one pharmaceutically acceptable excipient(s) and formulating the resulting sustained release components into a pharmaceutical dosage form. , Description:TECHNICAL FIELD
[001] The present disclosure relates generally to modified release pharmaceutical compositions of Memantine HCl extended release and Donepezil HCl immediate release pellets or pharmaceutically acceptable salts thereof. In particular, the compositions of invention are stable, possess improved formulation characteristics and also provide extended and/or immediate therapeutically effective plasma levels over the requisite time period. The invention also relates to processes of making such compositions.

BACKGROUND
[002] Memantine is an orally active NMDA (N-methyl-D-aspartate) receptor antagonist which acts by blocking the NMDA receptors in the brain. It blocks the excessive activity of glutamate, but still allows the normal activation of these receptors that occurs when the brain forms a memory. Therefore, it improves the brain functioning in Alzheimer's disease, and may also block the glutamate activity that could cause further damage to the brain cells. It has been also hypothesized that Memantine may not only be effective for the treatment of Alzheimer's disease (as well as Parkinson's and other neurological diseases), but may also be effective for the treatment of autism, Attention-Deficit/Hyperactivity Disorder (ADHD) and other autistic spectrum disorders. Memantine has the chemical name 3, 5-dimethyladamantan-lamine. Memantine hydrochloride is commercially available in the market in products sold under the trademark Namenda®. It is available for oral administration as capsule shaped film-coated tablets containing 5 g and 10 g of Memantine hydrochloride. Currently, a dosing regimen of Memantine twice a day is employed using immediate release tablets and once a day dosing regimen employed using sustained release tablets. In case, Namenda XR capsules are supplied for oral administration as 7, 14, 21, and 28 mg capsules. Each capsule contains extended release beads with the labeled amount of Memantine HCl

[003] Donepezil is a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the treatment of Alzheimer's disease where it is used to increase cortical acetylcholine. It has an oral bioavailability of 100% and easily crosses the blood-brain barrier. Because it has a half-life of about 70 hours, it can be taken once a day. Initial dose is 5 mg per day which can be increased to 10 mg per day after an adjustment period of at least 4 weeks. While the drug in a tablet or a granule form is currently indicated for mild to moderate Alzheimer's, there is also evidence from clinical trials that it may be effective for moderate to severe diseases, therefore many neurologists, psychiatrists and primary-care physicians use Donepezil in patients with Alzheimer's disease because of its acetylcholinesterase inhibiting action. Recently, a tablet which disintegrates in the mouth have been marketed for patients who have trouble swallowing, and transdermal administration by an ointment preparation has been proposed for cases in which oral administration is difficult.

[004] Memantine HCl is available as extended release pellets alone and in combination with Donepezil HCl in market. In combination, Memantine HCl is available as extended release and Donepezil HCl as immediate release powder mixture separately. In combination, it is available as capsules where Memantine extended-release (ER) pellets and Donepezil HCl immediate-release (IR) dry powder were mixed and filled in capsule.

[005] Memantine Hydrochloride ER and Donepezil Hydrochloride IR Pellets are manufactured by ALLERGAN SALES LLC under the brand name NAMZARIC. It was approved by FDA in Dec 23, 2014. It is a fixed-dose combination of Memantine extended-release (ER) and donepezil immediate-release (IR). Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist approved for treatment of Alzheimer’s disease. Currently manufactured drug formulations comprise Memantine HCl as extended-release pellets and Donepezil HCl as immediate-release pellets. The product commercially available is a combination of Memantine extended-release pellets mixed with Donepezil powder blend that is finally filled into capsules. Due to large variations in the particle sizes of Memantine pellets and Donepezil powder, there are always chances for segregation of powder. Donepezil is hygroscopic and susceptible for oxidation. This could be the major reason for the existing product being unable to be processes in a pellet form. Further, during different manufacturing process and exposure to air and moisture, the product gets degraded. Therefore, an existing and continual need for combined formulations comprising modified release of Memantine or its pharmaceutically acceptable salt along with immediate-release formulations of Donepezil or its pharmaceutically acceptable salt. Also there are several issues related to degradation of the product during stability and other issues like segregation during capsule filling process. i.e., mixing of Memantine HCl extended release with donepezil HCl immediate release pellets. Hence, even though several approaches have been suggested in the art, it is apparent to one skilled in the art that available technology for multistage release pharmaceutical dosage forms, still leaves a need to provide alternative and improved stabilized formulations of Memantine and Donepezil with reliable absorption over a targeted period of time besides possessing good formulation characteristics desired for bulk manufacturing of the product.

[006] WO/2005072705 discloses a compound preparation of memantine hydrochloride and donepezil hydrochloride, wherein memantine hydrochloride is a sustained-release pellet, and donepezil hydrochloride is an immediate release pellet, which is co-filled in a capsule. The industrial scale-up of such a process is difficult, and the requirements for capsule filling equipment are relatively high. In this citation, Lactose is employed as a supplementary material to prepare the donepezil particles. Lactose is prone to Maillard reaction to Memantine hydrochloride, which produces lactose adduct, which is not conducive to the stability of the preparation. CN105816441A also discloses a Memantine hydrochloride and donepezil hydrochloride composite preparation. Memantine hydrochloride and donepezil hydrochloride serve as medicine active components and wrap a pellet together, the slow release of Memantine hydrochloride and the rapid release of donepezil hydrochloride are controlled in a multi-layer coating mode, finally the preparation is filled in a capsule. Other relevant prior arts in the technical filed of interest include: EP2243475, US8815288, US6682759 and US20110171302.

[007] Based on the aforementioned discussion, there still remains an unmet need in the art to ameliorate or overcome the lacunae in the process of manufacture/preparation of stabilized combined multistage release pharmaceutical dosage forms. The above discussion of documents is included solely for the purpose of providing a context for the present invention.

BRIEF SUMMARY
[008] The following presents a simplified summary of the disclosure in order to provide a basic understanding to the reader. This summary is not an extensive overview of the disclosure and it does not identify key/critical elements of the invention or delineate the scope of the invention. Its sole purpose is to present some concepts disclosed herein in a simplified form as a prelude to the more detailed description that is presented later. A more complete appreciation of the present invention and the scope thereof can be obtained from the accompanying drawings which are briefly summarized below and the following detailed description of the presently preferred embodiments.

[009] An objective of the present disclosure is directed towards modified release pharmaceutical compositions of Memantine HCl extended release and Donepezil HCl immediate release pellets or pharmaceutically acceptable salts thereof.

[010] Another objective of the present disclosure is directed towards process of manufacture/preparation of modified release pharmaceutical compositions of Memantine HCl extended release and Donepezil HCl immediate release pellets or pharmaceutically acceptable salts thereof.

[011] In another aspect of the present disclosure, Donepezil HCl is coated as over coat on seal coated Memantine HCl extended release pellets and both are separated by a seal coat using different solvent systems to reduce degradation and to enhance stability.

[012] In another aspect of invention, the object of the disclosure is to avoid issues related to degradation of the pharmaceutical product during stability and issues like segregation during capsule filling stage. i.e., mixing of Memantine HCl extended release with donepezil HCl immediate release pellets and to overcome segregation issues during capsule filling process.

[013] In another aspect of the invention, the absence or lack of water in the solvent systems used to prepare a stable modified release pharmaceutical composition of Memantine HCl extended release and Donepezil HCl immediate release. Particularly, the stability of the Donepezil HCl immediate release component is attributed to the lack of water in the solvent systems used herein.

[014] In yet another aspect of invention, a modified release pharmaceutical composition of Memantine HCl extended release and Donepezil HCl immediate release is presented in a single pellet, to avoid the potential segregation issues arising due to combining individual pellets of Memantine HCl and dry mix powder of Donepezil HCl.

[015] According to an exemplary embodiment of the present disclosure, a modified release pharmaceutical composition of Memantine HCl extended-release (ER) and donepezil HCl immediate-release (IR) comprising:
a seal coated core;
a first drug layer applied to the seal coated core comprising Memantine HCl extended-release (ER) with at least one pharmaceutically acceptable excipient(s) to provide a drug coated pellet;
a sub coat applied on the drug coated pellet using one or more rate controlling polymers to provide a sub-coated pellet;
a polymer coat applied on the sub-coated pellet using the one or more rate controlling polymers to provide a polymer coated pellet;
a second drug layer of Memantine HCl extended-release (ER) with at least one pharmaceutically acceptable excipient(s) applied on the polymer coated pellet to provide an intermediate 1;
a second seal coat applied on the intermediate 1 to provide a seal coated intermediate 1; and
at least one coat of Donepezil HCl immediate-release (IR) drug layer with at least one pharmaceutically acceptable excipient(s) coated on the seal coated intermediate 1 to provide the modified release pharmaceutical composition of Memantine HCl extended-release (ER) and Donepezil HCl immediate-release (IR).

[016] According to an exemplary embodiment of the present disclosure, process for the preparation of a modified release pharmaceutical composition, the process comprising:
(a) providing a plurality of Memantine HCl extended-release (ER) with at least one pharmaceutically acceptable excipient(s);
(b) providing a plurality of Donepezil HCl immediate-release (IR) drug layer with at least one pharmaceutically acceptable excipient(s); and
(c) coating the of Donepezil HCl immediate-release (IR) drug layer with at least one pharmaceutically acceptable excipient(s) over the Memantine HCl extended-release (ER) with at least one pharmaceutically acceptable excipient(s) and formulating the resulting sustained release components into a pharmaceutical dosage form.

[017] Furthermore, the objects and advantages of this invention will become apparent from the following description.

BRIEF DESCRIPTION OF THE DRAWINGS
[018] Other objects and advantages of the present invention will become apparent to those skilled in the art upon reading the following detailed description of the preferred embodiments, in conjunction with the accompanying drawings, wherein like reference numerals have been used to designate like elements, and wherein:

[019] FIG. 1 is a diagram 100 depicting a pictorial representation of of modified release pharmaceutical composition of Memantine HCl extended-release (ER) and donepezil HCl immediate-release (IR) pellets, in accordance with one or more exemplary embodiments.

[020] FIG. 2 is a diagram 200 depicting a process for the preparation of a modified release pharmaceutical composition of Memantine HCl extended-release (ER) and donepezil HCl immediate-release (IR) pellets, in accordance with one or more exemplary embodiments.

DETAILED DESCRIPTION
[021] It is to be understood that the present disclosure is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. The present disclosure is capable of other embodiments and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.

[022] The use of “including”, “comprising” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. The terms “a” and “an” herein do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. Further, the use of terms “first”, “second”, and “third”, and the like, herein do not denote any order, quantity, or importance, but rather are used to distinguish one element from another.

[023] All publications herein are incorporated by reference to the same extent as that clearly to be included by reference if each individual publication or patent application, and individually indicated. The following description includes information that may be useful for understanding the present invention. This does not admitted that any of the information is prior art, or to be or being specifically related to the invention claimed herein or implicit any prior art publication is referred to as provided herein.

[024] The inventors of the present invention have surprisingly found that it is possible to develop a stable and multiple phase release formulation of Memantine or salts thereof combined with Donepezil or salts thereof which is suitable for daily administration with reliable absorption over a targeted period of time. The formulations according to the present invention also possess good formulation characteristics (such as flowability, compressibility, content uniformity etc.) desired for bulk manufacturing of the product. Multiple phase release formulations involve complex manufacturing process and hence require close monitoring of processing steps, particularly coating and compression of multiple unit components. For example, such multiple unit components are prone to sticking, picking and agglomeration during manufacturing of multiple phase release formulations, which ultimately can affect content uniformity of final dosage forms. The present inventors concomitantly have found that stabilized combined multistage release pharmaceutical dosage forms; particularly biphasic release dosage forms using pharmaceutically acceptable excipients in judicial amount may achieve desired release pattern of Donepezil and Memantine from the dosage forms.
[025] Donepezil is hygroscopic and susceptible for oxidation. During evaluation, the inventors identified that if it is exposed to moisture, it oxidizes and degrades further. This could be the major reason for the existing products to be not being processed into pellets or granules. Previously, a simple dry powder mix for Donepezil was prepared and filled into capsules along with Memantine extended release pellets. During different manufacturing processes, subsequent exposure to air and moisture, the product degrades further due to sensitivity towards oxidation and also due to its hygroscopic nature. The aforementioned problems in the state of art have been rectified in the present invention by using different solvent systems and by avoiding water in the manufacturing process. As both Donepezil and Memantine will be presented in a single pellet, it avoids the potential segregation issues with individual pellets of Memantine HCl and dry mix powder of Donepezil HCl.

[026] In particular, the inventors have found that if pharmaceutically acceptable binder in amount of 2% i.e., for a seal coating to separate 2 active drug parts. Further, the biphasic formulation comprising Memantine or salt thereof and Donepezil or salts thereof, the resulting formulation may exhibit excellent formulation characteristics simultaneously providing drug release over 12 hour. Such formulations may also remain stable over the storage period.

[027] Thus, the present invention provides a modified release pharmaceutical composition comprising memantine or salts thereof and Donepezil or salts thereof, one or more pharmaceutically acceptable binders and one or more pharmaceutically acceptable excipients, wherein composition exhibits biphasic release profile and the amount of the binder ranges from 0.3%-2.0% by weight of the composition. For example: binder percentage typically used in between memantine and donepezil parts is equal to or more than 2.0%. The modified release composition comprises drug containing sustained release components and immediate release components.

[028] The term "biphasic release" as used herein refers to two different phases of
release of Memantine and Donepezil from the composition, with or without a preceding lag time. The appearance of second phase of release may be detected with a sudden increase in the rate of release at the beginning of the second phase. This can be observed by a change in the slope of the cumulative drug release profile.

[029] The term "modified release pharmaceutical composition" as used hereinbefore and throughout the description includes dosage forms containing combination of components providing immediate release of Donepezil or salts thereof and sustained or controlled or delayed release of memantine or salts thereof from the dosage form.

[030] The term "controlled release" is intended to refer to non-immediate release of Memantine or salts thereof from the formulation.

[031] The term "sustained release" is used in its conventional sense to refer to a formulation that provides for gradual release of Memantine or salts thereof over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of Memantine over an extended time period.

[032] The term "delayed release" is used in its conventional sense to refer to a formulation in which there is a time delay between oral administration of the formulation and the release of Memantine or salts thereof. Delayed release may or may not involve gradual release of Memantine or salts thereof over an extended period of time, and thus may or may not be sustained release. For example, delayed release formulations of Memantine or salts thereof are enterically coated components.

[033] The term "component" as used hereinbefore and throughout the description refers to Memantine and/or Donepezil containing powder, particles, agglomerates, granules, pellets, microspheres, liposomes, sphericles, minitablets, microcapsules, tablets, cores and coats/layers on thereof or any solid physical form known to the person skilled in the art.

[034] The term "core" according to the invention an inert substance layered with memantine, optionally mixed with other pharmaceutically acceptable excipients, can be used as the core material for the further processing. The core can be homogenous or have an internal structure comprising pellets, tablets, minitablets, capsules, granules, beads or pills.

[035] The term "inert" is a pharmaceutical substance which is inactive in relation to the active ingredient and other pharmaceutically acceptable excipient(s). that is to say. it does not react with the active ingredient and other pharmaceutically acceptable excipient(s) in the conditions used in such a way that there is decomposition thereof. The inert substance can be but not limited to different oxides, celluloses, organic polymers, different inorganic salts, sugars, non-pareils. alone or in mixtures. Before the seeds are layered, the active substance may be mixed with one or more other pharmaceutically acceptable excipients.

[036] The term "Memantine" used throughout the specification refers to not only Memantine per se, but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof. It is also possible to use any salts and free base form of Memantine, including polymorphs, hydrates, solvates or amorphous forms. The preferred salt of Memantine is hydrochloride salt.

[037] The term "Donepezil" used throughout the specification refers to not only Donepezil per se, but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof. It is also possible to use any salts and free base form of Donepezil, including polymorphs, hydrates, solvates or amorphous forms. The preferred salt of Donepezil is hydrochloride salt.

[038] In an embodiment, the amount of Memantine or salt thereof in the sustained release components and Donepezil immediate release components of modified release composition ranges from about 5% to about 100% by weight and about 3% to about 100% by weight respectively.

[039] The modified release pharmaceutical composition or sustained release and immediate release components therein may be prepared by processes known to the person having ordinary skill in the art of pharmaceutical technology such as direct compression, wet or dry granulation, slugging, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion-spheronization, spray drying and solvent evaporation.

[040] Suitable "rate controlling polymers" may include one or more of hydrophilic and hydrophobic polymers or mixtures thereof.

[041] Suitable hydrophilic polymers may include one or more of cellulosic polymers/copolymers or its derivatives including methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose; polyethylene oxides, polyethylene glycols, chitosan, gums, starch derivatives, polyurethanes, galactomannans, polysaccharides, polyalcohols, acrylic acid or acrylamide derivatives and the like. The preferred hydrophilic polymer is hydroxypropyl methylcellulose/ Hypromellose E5 or any commercially available grade thereof such as Methocel.

[042] Suitable hydrophobic polymers include one or more of ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnauba wax, hydrogenated vegetable oil, glycerol monostearate, stearyl alcohol, glyceryl behenate, poly anhydrides, methyl acrylates and the like.

[043] The polymers used can also be eroding or non-eroding or combination of both.

[044] The polymers, which may be used for bio adhesion, are described below. Natural polymers include but are not limited to proteins (e.g., hydrophilic proteins), such as pectin, zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, chitosan, oligosaccharides and polysaccharides such as cellulose, dextrans, tamarind seed polysaccharide, gellan, carrageenan, xanthan gum, gum Arabic; hyaluronic acid, polyhyaluronic acid, alginic acid, sodium alginate.

[045] When the bio adhesive polymer is a synthetic polymer, the synthetic polymer is typically selected from but are not limited to polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes, polystyrene, polymers of acrylic and methacrylic esters, polylactides, poly(butyric acid), poly(valeric acid), poly(lactide-co-glycolide), polyanhydrides, polyorthoesters, poly(fumaric acid), poly(maleic acid), and blends and copolymers or mixtures thereof.

[046] Other polymers suitable for use in the invention include, but are not limited to, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxybutylmethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, alkyl phthalate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(Iauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly (ethylene terephthalate), polyvinyl acetate), polyvinyl chloride, polystyrene, polyvinyl pyrrolidone, and polyvinylphenol. Polylactides, polyglycolides and copolymers thereof, poly(ethylene terephthalate), poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), poly[lactide-coglycolide], polyanhydrides (e.g., poly(adipic anhydride)), polyorthoesters, blends and copolymers thereof. Another group of polymers suitable for use as bioadhesive polymers but not necessarily limited to polymers having a hydrophobic backbone with at least one hydrophobic group pendant from the backbone. Suitable hydrophobic groups are groups that are generally non-polar. The amount of rate controlling polymer in the modified release composition ranges from about 2% to about 20% by weight of the composition.

[047] Suitable "pharmaceutically acceptable binders" may include one or more of Methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, gum arabic, polymethacrylates, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, carrageenan, polyethylene oxide, waxes, pullulan, agar, tragacanth, veegum, pregelatinized starch, sodium alginate, gums, sugars such as sucrose, maltose, dextrose, lactose, amylase, synthetic resins and the like.

[048] The amount of binder for use in the modified release composition is more than 3%, preferably more that 1% by weight of the composition. The % of binders may range between 1%-3%. Preferable pharmaceutically acceptable binder is hydroxypropyl methylcellulose.

[049] It was also surprisingly found that pharmaceutically acceptable binder when used in amount of more than 1% by weight of the sustained release and/or immediate release component, the resulting formulation possess good formulation characteristics.

[050] In an embodiment, the amount of pharmaceutically acceptable binder in the sustained release component and immediate release component in the composition comprises more than 2% by weight and more than 1% by weight of composition respectively.

[051] In an embodiment, a stable modified release pharmaceutical composition comprising memantine or salts thereof and Donepezil or salts thereof, one or more pharmaceutically acceptable binder and one or more pharmaceutically acceptable excipients, wherein the composition retains at least 95% of the potency of the memantine or salts thereof and at least 95% of the potency of Donepezil or salts thereof in the pharmaceutical composition after storage for three months at 40° C and 75% relative humidity.

[052] In a further embodiment, a stabilized modified release pharmaceutical composition comprising memantine or salts thereof and Donepezil or salts thereof in accordance with the present invention comprises combination of high molecular weight acidic and basic substances.

[053] The term "acidic and basic substances" as used herein are high molecular weight substances which exhibits acidity and basicity respectively when dissolved or suspended in water. The preferred high molecular weight acidic and basic substances are polymers. However, it will be appreciated to the person skilled in the art that any substance imparting said property can be used as long as it stabilizes the modified release biphasic pharmaceutical composition.

[054] The pharmaceutically acceptable excipients may include one or more fillers, lubricants, disintegrants, glidants, colorants, sweeteners, plasticizers and the like.

[055] Suitable fillers may include, but not limited to one or more of microcrystalline cellulose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide; sugars such as lactose or sucrose; sugar alcohols such as mannitol, sorbitol, erythritol and the like.

[056] Suitable disintegrants may include, but not limited to one or more of croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone and the like.

[057] Suitable plasticizers may include, but not limited to one or more of glycerine fatty acid esters; triethyl citrate; propylene glycol; polyethylene glycol and the like.

[058] Suitable lubricants and glidants may include one or more of talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid,.hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, powdered cellulose, starch, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate, kaolin; and the like Suitable plasticizers may include, but not limited to one or more of polyols such as glycerol, propylene glycol, polyethylene glycol (PEG), urea, or other known plasticizers such as triethyl citrate, dibutyl or dimethyl phthalate or water.

[059] Suitable examples of colorants include, but not limited to one or more of non-water soluble lake pigments; neutral pigments; yellow ferric oxide; red ferric oxide; black iron oxide and the like.
[060] The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention

[061] Example 1: Memantine HCl Extended Release and Donepezil HCl Immediate Release Pellets with usage of Purified water
TABLE:1
Formula composition
S. No. Name of Pharmaceutical Ingredient Pharmacopoeial Reference mg/unit
28/10
SEAL COATING STAGE
1 Sugar Spheres [ASTM#20/25] IH 129.30
2 Hypromellose [HPMC E-5] BP 3.87
3 Purified water BP 60.63
Total weight, mg 133.17
DRUG LOADING STAGE – 1
4 Seal Coated sugar spheres [ASTM#20/25] IH ----
5 Memantine HCl USP 26.60
6 Hypromellose E5 BP 13.30
7 Purified Talc BP 2.66
8 Iso Propyl alcohol (IPA) BP 191.52
9 Purified Water IH 191.52
Total weight, mg 175.73
SUB COATING
10 Hypromellose [HPMC E-5] BP 7.68
11 Tri ethyl citrate (TEC) BP 0.73
12 Purified Talc BP 1.54
13 Purified water IH 155.23
Total weight, mg 185.68
POLYMER LOADING STAGE(6.50%w/w build up )13.42% solid content
14 Ethyl cellulose 7cps BP 7.79
15 Hypromellose [HPMC E-5] BP 1.56
16 Triethyl citrate BP 0.78
17 Purified Talc BP 1.95
18 Isopropyl Alcohol [IPA] BP 27.28
19 Acetone BP 42.87
20 Purified Water IH 7.79
Total weight, mg 197.76
DRUG LOADING STAGE – 2
21 Memantine HCl USP 1.40
22 Hypromellose E5 BP 0.70
23 Purified Talc BP 0.14
24 Iso Propyl alcohol (IPA) BP 10.08
25 Purified Water IH 10.08
Total 200.00
SEAL COATING STAGE
26 Hypromellose [HPMC E-5] BP 3.08
27 Tri ethyl citrate (TEC) BP 0.31
28 Purified Talc BP 0.62
29 Purified water IH 62.73
Total 204.00
DRUG LOADING STAGE – 3
30 Donepezil Hydrochloride USP 10.00
31 Hypromellose [HPMC E-5] BP 5.00
32 Purified Talc BP 1.00
33 Iso Propyl alcohol (IPA) BP 72.00
34 Purified water BP 72.00
Total 220.00

[062] Manufacturing Process /Procedure:
1.1 Seal coating on sugar spheres
• Transfer purified water into stainless steel/plastic beaker and keep under stirring.
• Add Hypromellose E5 premium into the vertex with continuous stirring until a clear solution is obtained.
• Sift the seal coated Pellets through ASTM #20/25 collect 20 passed and #25 mesh retained pellets.
• Spray the solution over #20/25sugar sphere at 40°C in FBC.

Drying:
• After coating dry the pellets for 30 min under fluidization as mentioned in above process parameter table.
• Sift the seal coated Pellets through ASTM #20 followed by #25 meshes and collect 20 passed and #25 mesh retained pellets.
1.2 Drug layering stage -1
Drug layering solution Preparation:
• Transfer the Purified water into a stainless steel/plastic vessel and under continuous stirring.
• Add Hypromellose E5 premium into the vertex with continuous stirring until a clear solution is obtained.
• Accurately add dispensed quantity of API to the vertex of IPA under continuous stirring for 10-15 minutes.
• To the above solution HPMC E5 solution was added with continuous stirring until a clear solution is obtained.
• Accurately add dispensed quantity of purified talc to the above solution under continuous stirring
• Filter the dispersion through ASTM #40 mesh filter cloth.

Spraying:
• Load seal coated sugar spheres (#20/25) into fluid bed processer bowl and perform pre heating at 40°C mentioned in the process parameters for drug layering.
• Start spraying the drug dispersion on preheated pellets seal coated sugar sphere at 35°C.
Drying:
• After completion of spraying, dry the drug coated spheres for about 30 minutes under fluidization at 40°C. Unload the dried drug coated spheres after cooling it to room temperature and check the weight.
Note: Sift the drug layering pellets through ASTM# 18 and #30mesh. Collect #18 passed and #30 retained pellets.

1.3 Sub coating:
• Transfer purified water into stainless steel/plastic beaker and keep under stirring.
• Add Hypromellose E5 premium into the vertex with continuous stirring until a clear solution is obtained.
• Add Triethyl Citrate to the above solution under continuous stirring.
• Add purified talc to the above solution under continuous stirring.
• Filter the dispersion through ASTM #40 mesh filter cloth.
• Preheat the equipment at 40°C.
Spraying and Drying:
• Spray the solution on pellets at 40°C and after coating dry the pellets for 30 mins under fluidization as mentioned in above process parameter table.
1.4 Polymer layering stage
• Transfer the Purified water into a stainless steel/plastic vessel and under continuous stirring.
• Add Hypromellose E5 premium into the vertex with continuous stirring until a clear solution is obtained.
• Accurately add dispensed quantity of Ethyl cellulose 7cps to the vertex of IPA under continuous stirring for 20 minutes.
• To the above solution HPMC E5 solution was added with continuous stirring until a clear solution is obtained.
• Add Triethyl Citrate to the above solution under continuous stirring.
• Add purified talc to the above solution under continuous stirring.
• Filter the dispersion through ASTM #40 mesh filter cloth.
• Preheat the equipment at 40°C.
Drying:
• Spray the solution on pellets at 35°C and after completion of spraying, dry the drug coated spheres for about 45 minutes under fluidization at 40°C. Unload the dried drug coated spheres after cooling it to room temperature and check the weight.
Note: Sift the drug layering pellets through ASTM# 16 and #25mesh. Collect #16 passed and #25 retained pellets.

1.5 Drug layering stage-2

• Transfer the Purified water into a stainless steel/plastic vessel and under continuous stirring.
• Add Hypromellose E5 premium into the vertex with continuous stirring until a clear solution is obtained.
• Accurately add dispensed quantity of API to the vertex of IPA under continuous stirring for 10-15 minutes.
• To the above solution HPMC E5 solution was added with continuous stirring until a clear solution is obtained.
• Accurately add dispensed quantity of purified talc to the above solution under continuous stirring
• Filter the dispersion through ASTM #40 mesh filter cloth.

Spraying:
• Load sub coated pellets (#16/25) into fluid bed processer bowl and Preheat the pellets at 40°C.
• Start spraying the drug dispersion at 40°C on preheated sub coated pellets.
Drying:
• After completion of spraying, dry the drug coated spheres for about 30 minutes under fluidization at 40°C. Unload the dried drug coated spheres after cooling it to room temperature and check the weight.
Note: Sift the drug layering pellets through ASTM# 16 and #25mesh. Collect #16 passed and #25 retained pellets.
1.6 Seal Coating

• Transfer purified water into stainless steel/plastic beaker and keep under stirring.
• Add Hypromellose E5 premium into the vertex with continuous stirring until a clear solution is obtained.
• Add Triethyl Citrate to the above solution under continuous stirring.
• Add purified talc to the above solution under continuous stirring
• Filter the dispersion through ASTM #40 mesh filter cloth.
• Preheat the equipment at 40°C.

Drying:
• Spray the solution at 40°C and after completion of spraying, dry the drug coated spheres for about 30 minutes under fluidization at 40°C. Unload the dried drug coated spheres after cooling it to room temperature and check the weight.
1.7 Drug layering stage-3

• Transfer purified water into stainless steel/plastic beaker and keep under stirring.
• Add Hypromellose E5 premium into the vertex with continuous stirring until a clear solution is obtained.
• Accurately add dispensed quantity of API to the vertex of IPA under continuous stirring till a clear solution is obtained.
• Add Hypromellose E5 premium solution to the above solution under stirring.
• Add purified talc to the above solution under continuous stirring.
• Filter the dispersion through ASTM #40 mesh filter cloth.
• Preheat the equipment at 40°C.
Drying:
• Spray the solution at 40°C and after completion of spraying, dry the drug coated spheres for about 40 minutes under fluidization at 40°C. Unload the dried drug coated spheres after cooling it to room temperature and check the weight.
Note: Sift the drug layering pellets through ASTM# 16and #25mesh. Collect #16 passed and #25 retained pellets. The pellets manufactured were tested in stress condition (50°C/75%Relative Humidity) and stability condition (40°C/75%Relative Humidity).

[063] Stress study data: Stress study is evaluated for donepezil HCl drug degradation. Stability at accelerated condition tested for both drug substances. The data is as mentioned below.

TABLE 2: Stress study data (50°C/75%Relative Humidity):
Stress study data
Parameters Specification Initial 7 Days 15 Days
Related substances
Donepezil open ring NMT-0.5% ND 0.26 0.4
Desbenzyl donepezil NMT-0.5% ND 0.19 0.25
Hydroxy donepezil NMT -0.5% 0.01 0.60 0.77
Donepezil related compound –A NMT -0.5% ND 0.01 0.03
Individual unidentified impurity NMT-0.2% 0.06 0.11 0.31
Donepezil N-Oxide NMT -0.5% 0.01 0.60 0.78
Total impurities NMT 2.0% 0.1 2.7 3.6

[064] TABLE 3: Stability Data-Accelerated Condition (40°C/75%RH)
S.No Test Specification Initial 1M 2M 3 M
1 Description White to off white color pellets Off white Off white Light yellow Light yellow
2 Loss on drying (%w/w) NMT 2.5 1.80 2.3 1.9 2.2
3
Dissolution-Memantine HCl (%) 1st hr (NMT 25.0) 10.0 11.9 9.4 11.2
4th hr (25-50) 45.1 49.5 47.7 51.3
8th hr (60-90) 76.9 85.9 80.4 85.0
12th hr (NLT 80%) 83.9 96.5 93.2 100.9
4 Assay-Memantine HCl (% w/w) 11.43-13.97 11.93 11.84 11.76 12.13
5 Organic impurities by HPLC –Memantine HCl (% w/w) Memantine related compound E NMT0.3
Memantine related compound A NMT 0.15
Memantine related compound B NMT 0.15
Memantine related compound C NMT 0.15 Memantine related compound D NMT 0.3
Any unspecified impurity NMT 0.2
Total impurities NMT 1.0 0.01

ND

ND

ND

ND

0.03 0.06 0.004

ND

ND

0.007

ND

0.02 0.03 0.009

ND

ND

0.012

ND

0.03 0.05 0.018

ND

ND

0.01

ND

0.03 0.06
6 Assay-Donepezil HCl (% w/w) 4.05-4.95 4.56 4.68 4.54 4.39
7 Dissolution- Donepezil HCl (%) NLT 85%-30 Min 100.3 97.3 97.3 94.7
8 Organic impurities by HPLC –Donepezil HCl (% w/w) Desbenzyl donepezil- NMT0.2
Hydroxy Donepezil- NMT 0.2
Related comp-A- NMT 0.2
Donepezil-N-Oxide- NMT 0.2
Any unspecified Impurity-NMT 0.2
Total Impurities- NMT 1.0
ND
ND
ND
-
LOQ

0.05 0.004
0.000
0.000
0.000
0.047

0.054 0.120
0.210
0.000
0.236
0.120

0.899 0.2351
0.3485
0.0000
0.3084
0.0573

1.0894

[065] Donepezil drug degradation is observed and total impurities were increased from 0.1% to 3.6% from initial to 15 days under stress study condition (50°C/75%Relative Humidity). Total impurities are increased from 0.05% to 1.089% from initial to 3 months under accelerated condition (40°C/75%RH).

[066] Confirmation of Donepezil HCl drug degradation:
To check and confirm the donepezil drug degradation with involvement of purified water in the composition, binary mixtures study is performed. Binary mixtures were prepared to confirm the impact of solvent systems like Purified water and Isopropyl alcohol and other excipients like hydroxypropyl methyl cellulose involved in Donepezil HCl composition.
TABLE 4: Stress study of Donepezil HCl at (50°C/75%RH)
Stress study (50°C/75%RH) Total impurities
Material Name Initial 7 days 15 days 30 days
API (Donepezil HCl) Not detected 0.048 0.058 0.05
API + water 0.04 0.06 6.13 6.29
API + water + HPMC E5 0.03 1.15 1.42 2.17
API+HPMC E5 0.05 0.05 0.06 0.06
API+IPA 0.04 0.04 0.04 0.04
API+HPMC E5+ IPA 0.05 0.04 0.05 0.05
The drug degradation data from binary mixtures confirms the involvement of purified water in drug degradation and solvent other than purified water like Isopropyl alcohol useful in drug stabilization by overcoming drug degradation.
[067] Donepezil HCl Immediate release pellets with removal of purified water: Donepezil HCl immediate release pellets were developed considering the binary mixtures stress study data with usage of solvent systems improves the drug product stability. The formula is mentioned below.
TABLE 5:
S. No. Name of Material Pharmacopoeial Reference mg/unit
SEAL COATING STAGE
1 Sugar Spheres [ASTM#20/25] IH 49.0
2 Hypromellose [HPMC E-5] BP 1.47
3 Purified water BP 24.50
Total 50.47
DRUG LOADING STAGE – 1
4 Seal Coated sugar spheres [ASTM#20/25] IH --
5 Memantine HCl USP 10.00
6 Hypromellose E5 BP 5.16
7 Purified Talc BP 1.0
8 Iso Propyl alcohol (IPA) BP 122.40
9 Dichloromethane IH 21.60
Total 66.63

TABLE 6: Donepezil HCl IR Pellets drug product stress study and stability study performed and data is mentioned below.
Donepezil HCl 15% IR pellets
Condition Specification Initial Stress study
(50°C/75%RH) Accelerated
(40°C/75%RH)
Related substances 7 days 15 days 30 days 1M 2M 3M 6M
Donepezil open ring NMT-0.5% 0.04 0.00 0.04 0.04 0.05 0.09 0.09 0.08
Desbenzyl donepezil NMT-0.5% 0.00 0.00 0.00 0.01 0.01 0.01 0.02 0.00
Hydroxy donepezil NMT -0.5% 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
Donepezil related compound -A NMT -0.5% 0.00 0.04 0.00 0.00 0.00 0.00 0.00 0.00
Individual unidentified impurity NMT-0.2% 0.00 0.00 0.00 0.01 0.00 0.00 0.00 0.00
Donepezil N-Oxide NMT -0.5% 0.00 0.00 0.00 0.00 0.00 0.01 0.01 0.00
Total impurities NMT 2.0% 0.04 0.04 0.04 0.05 0.06 0.11 0.12 0.08

[068] Donepezil drug degradation was not observed with the solvent systems used and total impurities were observed from 0.04% to 0.05% from initial to 30 days under stress study condition (50°C/75%RH). Total impurities are observed from 0.04% to 0.12% from initial to 6 months under accelerated condition (40°C/75%RH). From the stress study and stability study data performed, we can conclude that donepezil HCl is stabilized with removal of purified water. Donepezil HCl IR Pellets were stabilized with usage of different solvent systems and the composition is finalized for application on seal coated Memantine HCl ER pellets.

[069] EXAMPLE 2: Memantine Hydrochloride 12.72 % Extended Release and Donepezil Hydrochloride 4.55% Immediate Release Pellets
A combination system of Memantine HCl Extended Release and Donepezil HCl Immediate Release pellets are developed by coating donepezil HCl on Memantine HCl ER Pellets. Both active layers are separated by seal coating. The potential advantages with the present invention includes avoid of mixing of two different dosage form of different actives and to overcome the potential segregation issues.

The formula and manufacturing process mentioned below.
TABLE 7: Formula
Formula composition
S. No. Name of Pharmaceutical Ingredient Pharmacopoeial Reference mg/unit
28/10
SEAL COATING STAGE
1 Sugar Spheres [ASTM#20/25] IH 129.30
2 Hypromellose [HPMC E-5] BP 3.87
3 Purified water BP 60.63
Total weight, mg 133.17
DRUG LOADING STAGE – 1
4 Seal Coated sugar spheres [ASTM#20/25] IH ----
5 Memantine HCl USP 26.60
6 Hypromellose E5 BP 13.30
7 Purified Talc BP 2.66
8 Iso Propyl alcohol (IPA) BP 191.52
9 Purified Water IH 191.52
Total weight, mg 175.73
SUB COATING
10 Hypromellose [HPMC E-5] BP 7.68
11 Tri ethyl citrate (TEC) BP 0.73
12 Purified Talc BP 1.54
13 Purified water IH 155.23
Total weight, mg 185.68
POLYMER LOADING STAGE(6.50%w/w build up )13.42% solid content
14 Ethyl cellulose 7cps BP 7.79
15 Hypromellose [HPMC E-5] BP 1.56
16 Triethyl citrate BP 0.78
17 Purified Talc BP 1.95
18 Isopropyl Alcohol [IPA] BP 27.28
19 Acetone BP 42.87
20 Purified Water IH 7.79
Total weight, mg 197.76
DRUG LOADING STAGE – 2
21 Memantine HCl USP 1.40
22 Hypromellose E5 BP 0.70
23 Purified Talc BP 0.14
24 Iso Propyl alcohol (IPA) BP 10.08
25 Purified Water IH 10.08
Total 200.00
SEAL COATING STAGE
26 Hypromellose [HPMC E-5] BP 3.08
27 Tri ethyl citrate (TEC) BP 0.31
28 Purified Talc BP 0.62
29 Purified water IH 62.73
Total 204.00
DRUG LOADING STAGE – 3
30 Donepezil Hydrochloride USP 10.00
31 Hypromellose [HPMC E-5] BP 5.00
32 Purified Talc BP 1.00
33 Iso Propyl alcohol (IPA) BP 72.00
34 Dichloromethane BP 72.00
Total 220.00

[070] Manufacturing Process/Procedure:
1.8 Seal coating on sugar spheres
• Transfer purified water into stainless steel/plastic beaker and keep under stirring.
• Add Hypromellose E5 premium into the vertex with continuous stirring until a clear solution is obtained.
• Sift the seal coated Pellets through ASTM #20/25 collect 20 passed and #25 mesh retained pellets.
• Spray the solution over #20/25sugar sphere at 40°C in FBC.

Drying:
• After coating dry the pellets for 30 min under fluidization as mentioned in above process parameter table.
• Sift the seal coated Pellets through ASTM #20 followed by #25 meshes and collect 20 passed and #25 mesh retained pellets.
1.9 Drug layering stage -1
Drug layering solution Preparation:
• Transfer the Purified water into a stainless steel/plastic vessel and under continuous stirring.
• Add Hypromellose E5 premium into the vertex with continuous stirring until a clear solution is obtained.
• Accurately add dispensed quantity of API to the vertex of IPA under continuous stirring for 10-15 minutes.
• To the above solution HPMC E5 solution was added with continuous stirring until a clear solution is obtained.
• Accurately add dispensed quantity of purified talc to the above solution under continuous stirring
• Filter the dispersion through ASTM #40 mesh filter cloth.
Spraying:
• Load seal coated sugar spheres (#20/25) into fluid bed processer bowl and perform pre heating at 40°C mentioned in the process parameters for drug layering.
• Start spraying the drug dispersion on preheated pellets seal coated sugar sphere at 35°C.
Drying:
• After completion of spraying, dry the drug coated spheres for about 30 minutes under fluidization at 40°C. Unload the dried drug coated spheres after cooling it to room temperature and check the weight.
Note: Sift the drug layering pellets through ASTM# 18 and #30mesh. Collect #18 passed and #30 retained pellets.

1.10 Sub coating:
• Transfer purified water into stainless steel/plastic beaker and keep under stirring.
• Add Hypromellose E5 premium into the vertex with continuous stirring until a clear solution is obtained.
• Add Triethyl Citrate to the above solution under continuous stirring.
• Add purified talc to the above solution under continuous stirring.
• Filter the dispersion through ASTM #40 mesh filter cloth.
• Preheat the equipment at 40°C.
Spraying and Drying:
• Spray the solution on pellets at 40°C and after coating dry the pellets for 30 mins under fluidization as mentioned in above process parameter table.
1.11 Polymer layering stage
• Transfer the Purified water into a stainless steel/plastic vessel and under continuous stirring.
• Add Hypromellose E5 premium into the vertex with continuous stirring until a clear solution is obtained.
• Accurately add dispensed quantity of Ethyl cellulose 7cps to the vertex of IPA under continuous stirring for 20 minutes.
• To the above solution HPMC E5 solution was added with continuous stirring until a clear solution is obtained.
• Add Triethyl Citrate to the above solution under continuous stirring.
• Add purified talc to the above solution under continuous stirring.
• Filter the dispersion through ASTM #40 mesh filter cloth.
• Preheat the equipment at 40°C.
Drying:
• Spray the solution on pellets at 35°C and after completion of spraying, dry the drug coated spheres for about 45 minutes under fluidization at 40°C. Unload the dried drug coated spheres after cooling it to room temperature and check the weight.
Note: Sift the drug layering pellets through ASTM# 16 and #25mesh. Collect #16 passed and #25 retained pellets.

1.12 Drug layering stage-2

• Transfer the Purified water into a stainless steel/plastic vessel and under continuous stirring.
• Add Hypromellose E5 premium into the vertex with continuous stirring until a clear solution is obtained.
• Accurately add dispensed quantity of API to the vertex of IPA under continuous stirring for 10-15 minutes.
• To the above solution HPMC E5 solution was added with continuous stirring until a clear solution is obtained.
• Accurately add dispensed quantity of purified talc to the above solution under continuous stirring
• Filter the dispersion through ASTM #40 mesh filter cloth.

Spraying:

• Load sub coated pellets (#16/25) into fluid bed processer bowl and preheat the pellets at 40°C.
• Start spraying the drug dispersion at 40°C on preheated sub coated pellets.
Drying:
• After completion of spraying, dry the drug coated spheres for about 30 minutes under fluidization at 40°C. Unload the dried drug coated spheres after cooling it to room temperature and check the weight.

Note: Sift the drug layering pellets through ASTM# 16 and #25mesh. Collect #16 passed and #25 retained pellets.
1.13 Seal Coating

• Transfer purified water into stainless steel/plastic beaker and keep under stirring.
• Add Hypromellose E5 premium into the vertex with continuous stirring until a clear solution is obtained.
• Add Triethyl Citrate to the above solution under continuous stirring.
• Add purified talc to the above solution under continuous stirring
• Filter the dispersion through ASTM #40 mesh filter cloth.
• Preheat the equipment at 40°C.
Drying:
• Spray the solution at 40°C and after completion of spraying, dry the drug coated spheres for about 30 minutes under fluidization at 40°C. Unload the dried drug coated spheres after cooling it to room temperature and check the weight.
1.14 Drug layering stage-3

• Transfer IPA into stainless steel/plastic beaker and keep under stirring.
• Add Hypromellose E5 premium into the vertex with continuous stirring until a clear solution is obtained.
• Accurately add dispensed quantity of API to the vertex of dichloromethane under continuous stirring till a clear solution is obtained.
• Add Hypromellose E5 premium solution to the above solution under stirring.
• Add purified talc to the above solution under continuous stirring.
• Filter the dispersion through ASTM #40 mesh filter cloth.
• Preheat the equipment at 40°C.
Drying:
• Spray the solution at 32°C and after completion of spraying, dry the drug coated spheres for about 40 minutes under fluidization at 40°C. Unload the dried drug coated spheres after cooling it to room temperature and check the weight.
Note: Sift the drug layering pellets through ASTM# 16and #25mesh. Collect #16 passed and #25 retained pellets.

The combination system of Memantine HCl Extended release and donepezil HCl immediate release pellets were loaded for stability and data is mentioned below.

TABLE 8: Stability data of Memantine Hydrochloride 12.72 % ER and Donepezil Hydrochloride 4.55% IR Pellets

Tests Specification Initial Accelerated condition (40°C/75%RH)
1M 3M
Description
White to off white color pellets
off white color pellets off white color pellets off white color pellets
Assay, Memantine HCl (%) 11.45-13.99 12.47 12.36 12.95
LOD (%) NMT-5.0 2.1 2.3 1.3
MC (%) NMT-5.0 2.8 3.9 2.2
Dissolution Time point (hrs) - Memantine Hydrochloride
1 NMT-25% 11.3 10.7 10.4
2 ------- 23.4 21.6 20.1
3 ------- 39.8 38.4 35.6
4 30-65% 56.1 54.5 50.4
6 ------- 80.6 79.9 76.3
8 NLT-60% 91.5 92.9 92.3
10 ------- 96.0 98.0 96.0
12 NLT-80% 97.3 97.2 98.0
Related Substances- Memantine Hydrochloride
Memantine RC-E NMT-0.3% ND ND 0.01
Highest unknown impurity NMT-0.2% 0.02 ND 0.02
Total impurities NMT-0.5% 0.08 ND 0.03
Donepezil Hydrochloride part
Assay-Donepezil HCl (%) 4.10-5.01 4.78 4.59 4.44
Dissolution Time point (mins)-Donepezil HCl
5 ------- 108.9 99.1 99.9
10 ------- 108.9 98.9 99.6
15 ------- 108.5 98.8 99.2
20 ------- 108.3 98.6 99.2
30 NLT-85% 109.3 98.5 98.8
60 ------- 108.5 98.5 98.2
Related Substances- Donepezil HCl
Desbenzyl Donepezil NMT-0.5% ND ND 0.07
Hydroxy Donepezil NMT-0.5% ND ND 0.08
Donepezil RC-A NMT-0.5% ND ND 0.02
Donepezil open ring NMT-0.5% 0.06 0.01 ND
Highest unknown impurity NMT-0.2% 0.01 0.01 0.08
Donepezil–N-Oxide NMT-0.5% ND 0.01 ND
Total impurities NMT-1.0% 0.07 0.11 0.33

[071] A combination system of Memantine HCl Extended release and Donepezil HCl immediate release pellets were manufactured and stability data was generated and the data is found satisfactory. The physical and chemical parameters were well maintained as per the specification limits at initial and stability time points performed. Donepezil drug degradation was not observed throughout the study time points performed and no significant changes were observed with the combination system of Memantine HCl ER and donepezil HCl IR pellets. So we can conclude that combination system of Memantine HCl ER and Donepezil HCl IR Pellets invented provides the advantages in avoid of potential segregation of two different dosage form. Finally, the combination system provides stabilized systems of two different dosage forms in a single unit. Particularly, the stability of the Donepezil HCl immediate release component is attributed to the lack of water in the solvent systems used herein.

[072] Referring to FIG. 1 is a diagram 100 depicting a pictorial representation of modified release pharmaceutical composition of Memantine HCl extended-release (ER) and donepezil HCl immediate-release (IR) pellets, in accordance with one or more exemplary embodiments. 100 represents a modified release pharmaceutical composition of Memantine HCl extended-release (ER) and donepezil HCl immediate-release (IR) pellet comprising, 102 an inert core, 104 a seal coat, 102 and 104 comprise a seal coated inert core, 106 is a first drug layer applied to the seal coated core comprising Memantine HCl extended-release (ER) with at least one pharmaceutically acceptable excipient(s) to provide a drug coated pellet, 108 is a sub coat applied on the drug coated pellet using one or more rate controlling polymers to provide a sub-coated pellet, 110 is a polymer coat applied on the sub-coated pellet using the one or more rate controlling polymers to provide a polymer coated pellet, 112 is a second drug layer of Memantine HCl extended-release (ER) with at least one pharmaceutically acceptable excipient(s) applied on the polymer coated pellet to provide an intermediate 1, 114 is a second seal coat applied on the intermediate 1 to provide a seal coated intermediate 1, 116 is at least one coat of Donepezil HCl immediate-release (IR) drug layer with at least one pharmaceutically acceptable excipient(s) coated on the seal coated intermediate 1 to provide the modified release pharmaceutical composition of Memantine HCl extended-release (ER) and Donepezil HCl immediate-release (IR) pellet.
[073] Referring to FIG. 2 is a diagram 200 depicting a process for the preparation of a modified release pharmaceutical composition of Memantine HCl extended-release (ER) and donepezil HCl immediate-release (IR) pellets, in accordance with one or more exemplary embodiments. The process starts at step 202 with seal coating of sugar spheres with hydroxypropyl methyl cellulose (HPMC E5) and drying the seal coated pellets (SEAL COATING STAGE). At step 204: Drug layering of Memantine HCl (Active 1) by spraying the Active 1 on seal coated pellets using HPMC E5 as binder to increase the drug adhesion on seal coated pellets and talc as anti-tacking agent to ensure the smooth process. (DRUG LOADING STAGE – 1). At step 206: sub coating of drug coated pellets using hydroxypropyl methyl cellulose (HPMC E5) prior to polymer coating ensures the smooth and uniform polymer coating. (SUB COATING STAGE). At step 208: polymer coating on sub coated pellets is performed for controlled drug release. (POLYMER COATING STAGE). At step 210: drug coating Memantine HCl (Active 1) on polymer coated pellets is performed. (DRUG LOADING STAGE – 2). At step 212: seal coating of Memantine HCl (Active 1) extended release pellets is performed prior to Donepezil HCl immediate release (Active 2) coating is useful in separation of two active pellets with different release profiles. (SEAL COATING STAGE). Finally at step 214: Donepezil HCl immediate release (Active 2) coating on seal coated Memantine extended release pellets. (DRUG LOADING STAGE – 3).

[074] Exemplary embodiments are described with reference drawings. Exemplary embodiments disclosed herein and the drawings are intended to be regarded in an illustrative rather than a restrictive sense.
[075] In an embodiment, a modified release pharmaceutical composition of Memantine HCl extended-release (ER) and donepezil HCl immediate-release (IR) comprising:
a seal coated core;
a first drug layer applied to the seal coated core comprising Memantine HCl extended-release (ER) with at least one pharmaceutically acceptable excipient(s) to provide a drug coated pellet;
a sub coat applied on the drug coated pellet using one or more rate controlling polymers to provide a sub-coated pellet;
a polymer coat applied on the sub-coated pellet using the one or more rate controlling polymers to provide a polymer coated pellet;
a second drug layer of Memantine HCl extended-release (ER) with at least one pharmaceutically acceptable excipient(s) applied on the polymer coated pellet to provide an intermediate 1;
a second seal coat applied on the intermediate 1 to provide a seal coated intermediate 1; and
at least one coat of Donepezil HCl immediate-release (IR) drug layer with at least one pharmaceutically acceptable excipient(s) coated on the seal coated intermediate 1 to provide the modified release pharmaceutical composition of Memantine HCl extended-release (ER) and Donepezil HCl immediate-release (IR).

[076] In an embodiment, the modified release pharmaceutical composition comprises a core, wherein the core comprises water soluble/insoluble inert cores coated with memantine extended-release (ER) or salts thereof.

[077] In an embodiment, the modified release pharmaceutical composition comprises a rate controlling polymer comprising one or more of ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides, methyl acrylates, alkyl phthalates, cellulose acetate phthalate, polyethylene oxides, and polyethylene glycols.
[078] In an embodiment, the modified release pharmaceutical composition comprises a pharmaceutically acceptable binder comprising one or more of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, gum arabic, polymethacrylates, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, carrageenan, polyethylene oxide, waxes, pullulan, agar, tragacanth, veegum, pregelatinized starch, sodium alginate, gums and sugars.

[079] In an embodiment, the modified release pharmaceutical composition comprising Memantine HCl extended-release (ER) comprises more than 1% by weight of one or more pharmaceutically acceptable binders.

[080] In an embodiment, the modified release pharmaceutical composition comprising Donepezil HCl immediate-release (IR) comprises more than 1% by weight of one or more pharmaceutically acceptable binders.

[081] In an embodiment, the modified release pharmaceutical composition is in the form of a tablet, a capsule, granules, pellets, caplets, minitablets, a capsule filled with minitablets and/or pellets, a multi-layer tablet, granules for suspension, or granules filled in a sachet.

[082] In an embodiment, the modified release pharmaceutical composition comprises about 4.5% -15% by weight of the immediate release component, and about 1-12% by weight of the sustained release components.

[083] In an embodiment, the modified release pharmaceutical composition comprises about 4% by weight of the immediate release component, and about 12% by weight of the sustained release components.

[084] In an embodiment, a process for the preparation of a modified release pharmaceutical composition, the process comprising:

(a) providing a plurality of Memantine HCl extended-release (ER) with at least one pharmaceutically acceptable excipient(s);

(b) providing a plurality of Donepezil HCl immediate-release (IR) drug layer with at least one pharmaceutically acceptable excipient(s); and

(c) coating the of Donepezil HCl immediate-release (IR) drug layer with at least one pharmaceutically acceptable excipient(s) over the Memantine HCl extended-release (ER) with at least one pharmaceutically acceptable excipient(s) and formulating the resulting sustained release components into a pharmaceutical dosage form.

[085] In an embodiment, the weight ratio of immediate and sustained release components present in the modified release pharmaceutical composition ranges from about 1:3 to about 1:30.
[086] More particularly, in an embodiment, the weight ratio of immediate and sustained release components present in the modified release pharmaceutical composition ranges from about 1:3 to about 1:20.
[087] In a further embodiment, the invention provides a method of treating Alzheimer's disease, Parkinson's and neurological diseases, autism, Attention Deficit/Hyperactivity disorder and autistic spectrum disorders comprises administering to a human patient in need thereof a modified release pharmaceutical composition comprising memantine or salts thereof and Donepezil or salts thereof, one or more pharmaceutically acceptable binder and one or more pharmaceutically acceptable excipients.

[088] Reference throughout this specification to “one embodiment”, “an embodiment”, or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, appearances of the phrases “in one embodiment”, “in an embodiment” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

[089] The present disclosure has been described in terms of certain preferred embodiments and illustrations thereof, other embodiments and modifications to preferred embodiments may be possible that are within the principles and spirit of the invention. The above descriptions and figures are therefore to be regarded as illustrative and not restrictive. Thus the scope of the present disclosure is defined by the appended claims and includes both combinations and sub combinations of the various features described herein above as well as variations and modifications thereof, which would occur to persons skilled in the art upon reading the foregoing description.