WO2021234475A1 - Compositions et procédés de libération modifiée de pastilles de chlorhydrate de mémantine à libération prolongée et de chlorhydrate de donépézil à libération immédiate - Google Patents

Compositions et procédés de libération modifiée de pastilles de chlorhydrate de mémantine à libération prolongée et de chlorhydrate de donépézil à libération immédiate Download PDF

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Publication number
WO2021234475A1
WO2021234475A1 PCT/IB2021/053269 IB2021053269W WO2021234475A1 WO 2021234475 A1 WO2021234475 A1 WO 2021234475A1 IB 2021053269 W IB2021053269 W IB 2021053269W WO 2021234475 A1 WO2021234475 A1 WO 2021234475A1
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release
memantine
donepezil
pharmaceutically acceptable
coated
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PCT/IB2021/053269
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English (en)
Inventor
Sreelatha Pathuru
G Basava Sankar
G S Valluri
Raghunadha C
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Pellets Pharma Limited
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Publication of WO2021234475A1 publication Critical patent/WO2021234475A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present disclosure relates generally to modified release pharmaceutical compositions of Memantine HC1 extended release and Donepezil HC1 immediate release pellets or pharmaceutically acceptable salts thereof.
  • 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.
  • 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.
  • ADHD Attention-Deficit/Hyperactivity Disorder
  • 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 HC1
  • 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.
  • Memantine HC1 is available as extended release pellets alone and in combination with Donepezil HC1 in market. In combination, Memantine HC1 is available as extended release and Donepezil HC1 as immediate release powder mixture separately. In combination, it is available as capsules where Memantine extended-release (ER) pellets and Donepezil HC1 immediate -release (IR) dry powder were mixed and filled in capsule.
  • ER Memantine extended-release
  • IR immediate -release
  • 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.
  • NMDA N-methyl-D-aspartate
  • Currently manufactured drug formulations comprise Memantine HC1 as extended-release pellets and Donepezil HC1 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.
  • Donepezil 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.
  • 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.
  • memantine hydrochloride is a sustained-release pellet
  • donepezil hydrochloride is an immediate release pellet, which is co-filled in a capsule.
  • 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.
  • CN 105816441 A 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.
  • An objective of the present disclosure is directed towards modified release pharmaceutical compositions of Memantine HC1 extended release and Donepezil HC1 immediate release pellets or pharmaceutically acceptable salts thereof.
  • Another objective of the present disclosure is directed towards process of manufacture/preparation of modified release pharmaceutical compositions of Memantine HC1 extended release and Donepezil HC1 immediate release pellets or pharmaceutically acceptable salts thereof.
  • Donepezil HC1 is coated as over coat on seal coated Memantine HC1 extended release pellets and both are separated by a seal coat using different solvent systems to reduce degradation and to enhance stability.
  • 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 HC1 extended release with donepezil HC1 immediate release pellets and to overcome segregation issues during capsule filling process.
  • a modified release pharmaceutical composition of Memantine HC1 extended release and Donepezil HC1 immediate release is presented in a single pellet, to avoid the potential segregation issues arising due to combining individual pellets of Memantine HC1 and dry mix powder of Donepezil HC1.
  • a modified release pharmaceutical composition of Memantine HC1 extended-release (ER) and donepezil HC1 immediate -release (IR) comprising: a seal coated core; a first drug layer applied to the seal coated core comprising Memantine HC1 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 HC1 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 HC1 immediate -release (IR) drug layer with at least one
  • process for the preparation of a modified release pharmaceutical composition comprising:
  • FIG. 1 is a diagram 100 depicting a pictorial representation of of modified release pharmaceutical composition of Memantine HC1 extended-release (ER) and donepezil HC1 immediate -release (IR) pellets, in accordance with one or more exemplary embodiments.
  • ER Memantine HC1 extended-release
  • IR donepezil HC1 immediate -release
  • FIG. 2 is a diagram 200 depicting a process for the preparation of a modified release pharmaceutical composition of Memantine HC1 extended-release (ER) and donepezil HC1 immediate -release (IR) pellets, in accordance with one or more exemplary embodiments.
  • ER Memantine HC1 extended-release
  • IR donepezil HC1 immediate -release
  • 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.
  • 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.
  • 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 HC1 and dry mix powder of Donepezil HC1.
  • 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.
  • 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.
  • the present invention provides a modified release pharmaceutical composition
  • 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.
  • 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.
  • biphasic release 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.
  • 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.
  • controlled release is intended to refer to non-immediate release of Memantine or salts thereof from the formulation.
  • 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.
  • 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.
  • delayed release formulations of Memantine or salts thereof are enterically coated components.
  • component 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.
  • core 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Suitable "rate controlling polymers” may include one or more of hydrophilic and hydrophobic polymers or mixtures thereof.
  • 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.
  • 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.
  • the polymers used can also be eroding or non-eroding or combination of both.
  • 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.
  • proteins e.g., hydrophilic proteins
  • 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • acidic and basic substances 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.
  • the pharmaceutically acceptable excipients may include one or more fillers, lubricants, disintegrants, glidants, colorants, sweeteners, plasticizers and the like.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 1 Memantine HC1 Extended Release and Donepezil HC1 Immediate Release Pellets with usage of Purified water
  • Stress study data Stress study is evaluated for donepezil HC1 drug degradation. Stability at accelerated condition tested for both drug substances. The data is as mentioned below.
  • 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 HC1 composition.
  • Donepezil HC1 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.
  • 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 HC1 is stabilized with removal of purified water. Donepezil HC1 IR Pellets were stabilized with usage of different solvent systems and the composition is finalized for application on seal coated Memantine HC1 ER pellets.
  • EXAMPLE 2 Memantine Hydrochloride 12.72 % Extended Release and Donepezil Hydrochloride 4.55 % Immediate Release Pellets
  • a combination system of Memantine HC1 Extended Release and Donepezil HC1 Immediate Release pellets are developed by coating donepezil HC1 on Memantine HC1 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.
  • 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.
  • 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.
  • Memantine HC1 Extended release and donepezil HC1 immediate release pellets were loaded for stability and data is mentioned below.
  • FIG. 1 is a diagram 100 depicting a pictorial representation of modified release pharmaceutical composition of Memantine HC1 extended-release (ER) and donepezil HC1 immediate -release (IR) pellets, in accordance with one or more exemplary embodiments.
  • ER Memantine HC1 extended-release
  • IR immediate -release
  • 100 represents a modified release pharmaceutical composition of Memantine HC1 extended-release (ER) and donepezil HC1 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 HC1 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 HC1 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
  • FIG. 2 is a diagram 200 depicting a process for the preparation of a modified release pharmaceutical composition of Memantine HC1 extended-release (ER) and donepezil HC1 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).
  • step 204 Drug layering of Memantine HC1 (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.
  • a modified release pharmaceutical composition of Memantine HC1 extended-release (ER) and donepezil HC1 immediate -release (IR) comprising: a seal coated core; a first drug layer applied to the seal coated core comprising Memantine HC1 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 HC1 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 HC1 immediate-release (IR) drug layer with at least one pharmaceutically acceptable excipient(s)
  • 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.
  • 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.
  • 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.
  • 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, poly
  • the modified release pharmaceutical composition comprising Memantine HC1 extended-release (ER) comprises more than 1% by weight of one or more pharmaceutically acceptable binders.
  • the modified release pharmaceutical composition comprising Donepezil HC1 immediate-release (IR) comprises more than 1% by weight of one or more pharmaceutically acceptable binders.
  • 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.
  • 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.
  • 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.
  • a process for the preparation of a modified release pharmaceutical composition comprising:
  • 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.
  • 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.
  • 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.

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Abstract

Des exemples de modes de réalisation de la présente divulgation sont relatifs à des compositions et des procédés de libération modifiée de pastilles de mémantine HCl-ER et de donépézil HCl-IR. La composition comprend : un noyau à enrobage étanche ; une première couche de médicament appliquée sur le noyau à enrobage étanche comprenant de la mémantine HCl-ER avec un(des) excipient(s) pharmaceutiquement acceptable(s) pour fournir une pastille enrobée de médicament ; une sous-couche appliquée sur la pastille enrobée de médicament à l'aide de polymères de régulation de vitesse pour fournir une pastille enrobée d'une sous-couche ; une couche de polymère appliquée sur la pastille enrobée d'une sous-couche à l'aide de polymères de régulation de vitesse pour fournir une pastille enrobée de polymère ; une seconde couche médicamenteuse de mémantine HCl-ER avec un(des) excipient(s) pharmaceutiquement acceptable(s) appliquée sur la pastille enrobée de polymère pour fournir un intermédiaire 1 ; une seconde couche d'étanchéité appliquée sur l'intermédiaire 1 pour fournir un intermédiaire 1 enrobé d'agent d'étanchéité ; et au moins un enrobage de couche médicamenteuse de donépézil HCl-IR avec un(des) excipient(s) pharmaceutiquement acceptable(s) appliqué sur l'intermédiaire 1 enrobé d'agent d'étanchéité pour fournir la composition pharmaceutique à libération modifiée.
PCT/IB2021/053269 2020-05-21 2021-04-21 Compositions et procédés de libération modifiée de pastilles de chlorhydrate de mémantine à libération prolongée et de chlorhydrate de donépézil à libération immédiate WO2021234475A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114010615A (zh) * 2021-12-28 2022-02-08 郑州大学第一附属医院 一种盐酸多奈哌齐缓释片及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8580858B2 (en) * 2004-11-23 2013-11-12 Adamas Pharmaceuticals, Inc. Compositions for the treatment of CNS-related conditions
WO2015037019A2 (fr) * 2013-09-15 2015-03-19 Rubicon Research Private Limited Formulations pharmaceutiques à libération modifiée
CN105816441A (zh) * 2016-05-31 2016-08-03 北京康立生医药技术开发有限公司 盐酸美金刚多奈哌齐复方制剂

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8580858B2 (en) * 2004-11-23 2013-11-12 Adamas Pharmaceuticals, Inc. Compositions for the treatment of CNS-related conditions
WO2015037019A2 (fr) * 2013-09-15 2015-03-19 Rubicon Research Private Limited Formulations pharmaceutiques à libération modifiée
CN105816441A (zh) * 2016-05-31 2016-08-03 北京康立生医药技术开发有限公司 盐酸美金刚多奈哌齐复方制剂

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114010615A (zh) * 2021-12-28 2022-02-08 郑州大学第一附属医院 一种盐酸多奈哌齐缓释片及其制备方法
CN114010615B (zh) * 2021-12-28 2023-03-24 郑州大学第一附属医院 一种盐酸多奈哌齐缓释片及其制备方法

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