WO2023128890A1

WO2023128890A1 - Donepezil – memantine extended release capsule composition

Info

Publication number: WO2023128890A1
Application number: PCT/TR2021/051560
Authority: WO
Inventors: Hatice ONCEL; Onur Pinarbasli; Feristah BILGIN; Gülistan Pelin GURBETOGLU; Nurdan ATILGAN; Asuman AYBEY DOGANAY; Nagehan SARRACOGLU
Original assignee: Ilko Ilac Sanayi Ve Ticaret A.S.
Priority date: 2021-12-28
Filing date: 2021-12-28
Publication date: 2023-07-06

Abstract

The present invention relates to obtain a fixed-dose capsule formulation comprising immediate release donepezil or a pharmaceutically acceptable salt thereof and extended release memantine or a pharmaceutically acceptable salt thereof as active substances. A process has beed developed for the preparation of said capsule having specific criteria of particle size distribution of granules/ pellets to provide an improved system for filling hard gelatin capsules with combined dissimilar materials.

Description

DONEPEZIL - MEMANTINE EXTENDED RELEASE CAPSULE COMPOSITION

Technical field:

The present invention relates to a pharmaceutical composition comprising donepezil and memantine or their pharmaceutically acceptable salts in combination, a process for the preparation of said pharmaceutical composition and a particle size distribution relation for the production of capsules comprising said composition with enhancing capsule filling efficiency.

Prior Art:

Donepezil is a reversible inhibitor of the acetylcholinesterase enzyme which is used to treat memory impairment in Alzheimer disease (AD). Its chemical name is (RS)-2-[(1- Benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one with a molecular formula C24H29NO3. Donepezil hydrochloride is a white crystalline powder and is freely soluble in chloroform, soluble in water and in glacial acetic acid, slightly soluble in ethanol and in acetonitrile, and practically insoluble in ethyl acetate and in n-hexane. Donepezil binds and reversibly inactivates the cholinesterases, thus inhibiting hydrolysis of acetylcholine. This increases acetylcholine concentrations at cholinergic synapses.

Memantine, which is another molecule used in the treatment of Alzheimer's disease, is a neuroprotective drug that is an antagonist of N-methyl-D-aspartate receptor (also known as the NMDA receptor) effective on dementia. NMDA receptor antagonists are a class of anesthetics that work to antagonize, or inhibit the action of the NMDA receptor. Its chemical name is 3,5-dimethyladamantan-1-amine with a molecular formula C₁₂H₂IN. Memantine HCI occurs as a fine white to off-white powder and is soluble in water. Memantine is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system by blocking NMDA receptors.

The chemical structures of donepezil and memantine are shown below.

Donepezil Memantine Donepezil was approved for medical use in the United States in 1996 for the treatment of dementia of the Alzheimer’s type and is available as 5 and 10 mg conventional immediate release tablets. In 2019, it was the 120th most commonly prescribed medication in the United States, with more than 5 million prescriptions. Extended- release form of donepezil was approved in combination with Memantine in 2014. Though it does not alter the progression of Alzheimer's disease, donepezil is effective in managing the symptoms of its associated dementia. The combination of donepezil and memantine, which is used to treat moderate to severe dementia of the Alzheimer's type, is in the market under the trade name Namzaric® Extended Release (ER) Capsule (Allergan Sales LLC). It is a capsule formulation consisting of memantine HCI extended release and donepezil HCI immediate release. The NMDA receptor antagonist is desirably provided in a controlled or extended release form with an immediate release component in order to maximize the therapeutic benefit of the NMDA receptor antagonist, while reducing unwanted side effects. It is available as four doses: 7mg/10mg, 14mg/10mg, 21mg/10mg, 28mg/10mg memantine HCI ER and donepezil HCI immediate release respectively.

The higher strength is for use in patients currently stabilized on memantine HCI (10 mg twice daily IR tablet or 28 mg once daily ER capsule) and donepezil HCI 10 mg. The lower strength is only for use in patients with severe renal impairment currently stabilized on memantine HCI (5 mg twice daily IR tablet or 14 mg once daily ER capsule) and donepezil 10 mg. The combined product administered as a once-daily fixed-dose combination regimen may simplify administration, increase compliance and adherence to treatment, and thus provide benefit for patients and their caregivers.

EP1509232B1 discloses the use of a composition comprising acetylcholinesterase inhibitor(s) and NMDA-antagonist(s) to treat mild cognitive impairment or dementia in connection with moderate to severe Alzheimer's. The combination use of donepezil and memantine are stated in this patent document.

EP1874282B1 relates to methods and compositions for treating CNS-related conditions, such as Alzheimer’s disease with using memantine and an acetylcholinesterase inhibitor (AChel) wherein said AChel is selected from donepezil, rivastigmine, galantamine, tacrine, metrifonate, or huperzine-A provided in an extended release dosage form. On the other hand, in the case of a fixed-dose composition containing two or more kinds of active substances, these substances may have different solubilities and pKa values to one another. Therefore, it is not always possible to combine drugs used in the same therapeutic field in a combined dosage form due to incompatibility problems. In the scientific literature, there are examples of unsuccessful results when compounds with different pharmacokinetic properties are used together to treat the same indications. In order to combine two or more different active substances in a single dosage form, the active substances should be compatible or formulated to be compatible with each other in order to obtain products with having uniform content, dissolution profile and stability in the desired ratio.

The combination of donepezil and memantine and its medical indications are already known. However, there are very few attempts to formulate uniform and stable combined formulations. The primary difficulty with this combination is the difference between the solubility and dissolution rates of these active substances. The solubility of memantine is much higher than the solubility of donepezil. This difference brings many undesirable consequences, especially in bioavailability, relating the inconsistent, inefficient and nonhomogeneous distribution of them. This situation also restrains the synergic effect of these two active agents in the combination.

A problem that arises in such combined product formulations is related to the content uniformity of the ingredients. Some components pose problems when filled into gelatin capsules. The different parts containing the active substances in the combined product may not always have the same amount and the same granule sizes. These active ingredients, together with the necessary excipients, can be obtained in the form of powders, granules or pellets with different sizes, which makes it very difficult to to produce content uniform dosage forms. In fact, this can sometimes pose a serious issue of content uniformity during the manufacture of final dosage forms.

In the present invention, it is aimed to obtain a pharmaceutical fixed dose capsule composition comprising extended release memantine HCI pellets and immediate release donepezil HCI granules having content uniform dosage form. The problems mentioned above were experienced during the capsule filling process due to the particle size differences between the obtained extended release pellets and the immediate release granules. This causes problems of poor capsule filling efficiency in the form of obtaining products with unsuitable content uniformity due to the fact that the amount of active substance in the content of the finished product is not in the desired amount. Therefore, an improved system and method is desirable for ensuring accurate dosage amounts in the production of oral dosage pharmaceutical products, particularly capsule products from pellets and granules with having different particle sizes.

The present invention addresses this problem and provides a solution thereto. In this way, the present inventors have developed a capsule formulation having specific particle size distribution of extended release memantine HCI pellets and immediate release donepezil HCI granules that is having enhanced capsule filling efficiency.

Description of the Invention:

The present invention relates to a pharmaceutical fixed-dose combination drug product comprising immediate release donepezil or a pharmaceutically acceptable salt thereof and extended release memantine or a pharmaceutically acceptable salt thereof as active substances and at least one pharmaceutically acceptable excipient.

The main object of the present invention is to obtain a fixed-dose capsule formulation comprising immediate release donepezil or a pharmaceutically acceptable salt thereof and extended release memantine or a pharmaceutically acceptable salt thereof as active substances having specific criteria of particle size distribution of granules/ pellets to provide an improved system for filling hard gelatin capsules with combined dissimilar materials in order to overcome content uniformity problems.

The present invention provides a pharmaceutical fixed-dose combination drug product comprising immediate release donepezil or a pharmaceutically acceptable salt thereof and extended release memantine or a pharmaceutically acceptable salt thereof, said fixed dose combination dosage form need to have several conditions in order to adapt donepezil granules and memantine pellets to be formulateable, wherein a) the particle size distribution of granules/ pellets should be adjusted to be able to fill effectively the space between the surfaces of both active substances, b) the Hausner factor of granules should be adjusted to be able to fill effectively the capsules, c) and consequently the qualitative and quantitative composition of the donepezil immediate release granules and memantine extended release pellets should be adjusted to allow the desired release rate of donepezil and memantine after dissolution of the capsule.

The present invention relates to obtain a fixed-dose capsule formulation comprising immediate release donepezil HCI granules and extended release memantine HCI pellets having particle size distribution of donepezil granules 200 pm < D90 < 500 pm to provide an improved system for filling hard gelatin capsules. Preferably, particle size distribution of donepezil granules are 250 pm < D90 < 500 pm, more preferably 250 pm < D90 < 400 pm to provide an improved system for filling hard gelatin capsules.

The present invention relates to obtain a fixed-dose capsule formulation comprising immediate release donepezil HCI granules and extended release memantine HCI pellets having particle size distribution of memantine pellets 800 pm < D90 < 1500 pm to provide an improved system for filling hard gelatin capsules. Preferably, particle size distribution of memantine pellets 900 pm < D90 < 1400 pm, more preferably 1000 pm < D90 < 1400 pm to provide an improved system for filling hard gelatin capsules.

The present invention also relates to obtain a fixed-dose capsule formulation comprising immediate release donepezil HCI granules and extended release memantine HCI pellets having Hausner factor of donepezil granules below 1.5, preferably below 1.4 to provide an improved system for filling hard gelatin capsules with combined dissimilar materials in order to overcome content uniformity problems.

Another object of the present invention is to obtain combination formulations of donepezil and memantine with high stability at accelerated and long term stability conditions.

It is the object of this disclosure to provide an oral dosage formulation comprising an extended release memantine with a dissolution rate of releasing more than 75% within 12 hours; an immediate-release donepezil with a dissolution rate of releasing more than 85% within 15 minutes.

According to one preferred embodiment, the amount of donepezil HCI is between 1- 10% by weight of the total composition.

According to this preferred embodiment, the amount of memantine HCI is between 1- 20% by weight of the total composition.

According to one embodiment, donepezil HCI is present in an amount of 5 to 20 mg in the total composition.

According this embodiment, memantine HCI is present in an amount of 3 to 50 mg in the total composition.

Various pharmaceutical products are packaged in the form of capsules for oral dosage and controlled release of a pharmaceutically active composition within an individual’s body. Typically a hard gelatin capsule is of the type comprising two part capsule shells, one of which is first filled with the formulation, then the other of which is connected thereto to close the capsule. In a typical capsule filling process, a source of particulate material, particles, pellets or granules to be filled into capsules is transferred by gravity from a hopper to a dosator. The dosator transfers the requisite amount of particles into an open capsule (e.g., an open shell portion of the capsule), and the open capsule is then sealed (e.g., by placing a shell cap over the open shell portion filled with particles). Depending upon the physical attributes of the particles to be capsule filling for the oral dosage product (e.g., variations in particle size, tackiness of the particulate material, irregularities in particle surface geometries, etc.), problems may occur in the transfer of the particles from the hopper to the dosator. When utilizing a pharmaceutical material that is difficult to capsule filling, especially having flowability problems, voids can be created in the hopper at locations previously occupied by particles transferred into the dosator, where the particulate material remaining within the hopper may not readily fill such voids. This can be a significant problem, for example, when the particles to be filled into capsules have differences in particle sizes, which cause the particles to frictionally adhere to each other, rather than sliding with respect to each other, as the particles are gravity fed from the hopper to the dosator. The generation of voids within the hopper in turn leads to significant and undesirable deviations in the amount of particles transferred to the dosator and, thus, to the pharmaceutical capsules being produced. In preparing product capsules with particulate material that is difficult to filling into capsules, the capsules tend to decrease in fill weight during the production process, with unfilled voids increasing in size until very little or no particles are transferred from the hopper to the dosator.

Many factors influence flowability of granules/ pellets/ powders, such as particle size, shape, density, adhesiveness, electrostatic chargeability, and other surface conditions of the particles. In particular, particle size and shape are the most important factors for flowability.

The occurrence of flowability problems and resultant problems with capsule production and content uniformity of the drug product are minimized or eliminated in accordance with the present invention by determining specific particle size distribution of extended release memantine HCI pellets and immediate release donepezil HCI granules.

In order to adapt donepezil granules and memantine pellets to be formulateable into a fixed dose combination dosage form, several conditions must be fulfilled, particularly a) the particle size distribution of granules/ pellets is so adjusted to be able to fill effectively the space between the surfaces of both active substances, b) the Hausner factor of granules is so adjusted to be able to fill effectively the capsules, c) and consequently the qualitative and quantitative composition of the donepezil immediate release granules and memantine extended release pellets are so adjusted to allow the desired release rate of donepezil and memantine after dissolution of the capsule.

The term "active substance" or "active ingredient" means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. In the present invention, the active ingredients are donepezil and memantine or their pharmaceutically acceptable salts, esters, and solvates thereof. Especially, in the present invention the active ingredients are donepezil hydrochloride monohydrate (donepezil HCI or donepezil) and memantine hydrochloride (memantine HCI or memantine).

The term “therapeutically effective amount” refers to the amount of either donepezil and memantine or salts thereof, or the combination, that is an amount sufficient to effect treatment, as defined herein, when administered to a subject in need of such treatment.

The term "immediate release dosage form” refers to a formulation of an active pharmaceutical ingredient that releases greater than 80%(Q) of the active pharmaceutical ingredient in 30 minutes in a USP dissolution method as described herein or by the manufacturer for a commercial product. In the present invention, the dissolution rate is fast enough that at least 85% of donepezil is released within 15 minutes.

As used herein the terms "extended release dosage form", "controlled release dosage form" and "sustained release dosage form" and like expressions are used interchangeably and include dosage forms where the active drug substance or substances are released of the therapeutic compound over an extended period of time. In the present invention, the dissolution rate is slow enough that at least 75% of memantine, a salt or a solvate thereof dissolves after 12 hours. In the present invention, the memantine, a salt or a solvate thereof will be released maximum of 25% after 1 hours; will be released between 50-85% within 6 hours, preferably 60-85% released within 6 hours and will be released at least 75% within 12 hours.

As used herein, “content uniformity” refers to the homogeneity of the donepezil and memantine content among unit dosage forms, e.g. capsules, after formulation. The term "particle size" relates in this invention to the D-value (e.g. the D90-value) of the volume averaged particle diameter, as determined by laser diffractometry.

Particle size distribution test is applied by laser diffraction in a dry dispersion system (Malvern Mastersizer-2000). Laser diffraction enables to measure particle size distributions by measuring the angular variation by scattering light intensity as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating the scattering pattern, using the Mie theory of light scattering. The particle size is reported as a volume equivalent sphere diameter.

The average particle diameter - also called DX value (e.g. the D90-value) of the integrated volume distribution - is likewise defined as the particle diameter, when exactly 90 vol.% of the particles have at least the diameter indicated and 10 vol.% of the particles have a larger diameter than the indicated value. Likewise, the D10-value determines the value, where 10 vol.% of the particles have the diameter value indicated, while the D50 value gives the median value of the particle diameters. Thus, these parameters provide an assessment of the particle size distribution.

Particle size distribution is a particularly sensitive test and very predictive in terms of addressing flowability problems for a given granule/ pellet. The target particle size distribution (PSD) of granules/ pellets can be selected and the appropriate particle size specifications should be established to control drug product quality and ensure manufacturing consistency. This target particle size distribution of granules/ pellets are specific for different granules/ pellets for capsule filling process and varies with the composition. Therefore, in the present invention the specific particle size distribution of extended release memantine HCI pellets and immediate release donepezil HCI granules are intended to be determined for effective capsule filling process.

Surprisingly, the inventors have found that the D90 value is a very sensitive indicator for the particle properties. When the size of the particles is too large or too small, negative effects can occur. For various applications, the size requirements for the final pellet/ particle granules must be met before being transferred to the capsule.

In addition to particle size distribution, the bulk density and tapped density are determined according to USP 24, Test 616 "Bulk Density and Tapped Density". In powder/ granule formulations particle size distribution, bulk density and tapped density properties are important to enhance the powder flowability, so as to guarantee the uniform filling of the capsules.

The term ‘Hausner-factor’ is the ratio of tapped density to bulk density. It is a measure of the compressibility of the respective powder. Usually, a high Hausner-factor indicates low flowability leading to weight differences of the tablets /capsules and therefore to a varying content of the active ingredient. This is a crucial factor for pharmaceutical drugs, since the appropriate dosage and thus bioequivalence with standard formulations must be ensured at any time.

In addition to active substances, there are other excipients like binder, diluents, disintegrant, lubricant, surfactants, solubilizing agents, coloring agents etc.

Useful binders include, but are not limited to, acacia, tragacanth, alginic acid, sodium alginate, carbomer, carboxymethylcellulose sodium, carrageenan, cellulose acetate phthalate, ceratonia, copovidone, dextrates, dextrin, dextrose, methylcellulose, ethylcellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose; hydroxyethyl methyl cellulose; hydroxypropyl cellulose; hydroxypropyl starch; hypromellose, gelatin, starch, sucrose, lactose, magnesium aluminum silicate, maltodextrin, maltose, microcrystalline cellulose, polyvinyl pyrrolidone, polyacrylamide, povidone and pregelatinized starch.

Useful diluents include, but are not limited to, ammonium alginate, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, cellulose, cellulose acetate, compressible sugar, dextrates, dextrin, dextrose, erythritol; ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, lactitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, microcrystalline cellulose, polydextrose, polymethacrylates, sodium chloride, sorbitol, starch, sucrose, Arbocel A300®; Ludipress®; and Super Tab®. In certain examples, the sustained-release portion is prepared by mixing memantine, a salt, a solvate or a mixture thereof with microcrystalline cellulose (e.g., Celphere® CP708), and at least one other matrix polymer as described above, to form memantine containing granules or pellets. Then, each of the memantine containing pellets is coated with a sustained- release fillm containing at least a matrix polymer described above (e.g., Eudragit®), a diluent (e. g., talc) and a stabilizer (e.g., triethyl citrate) to produce the sustained- release portion or the SR portion. Examples of disintegrants include, but are not limited to, cross-linked polyvinyl pyrrolidone or crospovidone, starch derivatives such as carboxy methyl cellulose and cellulose derivatives; calcium alginate; carboxymethylcellulose calcium; carboxymethylcellulose sodium; croscarmellose sodium; docusate sodium; hydroxypropylcellulose; magnesium aluminum silicate; methylcellulose; polacrilin potassium; sodium alginate; sodium starch glycolate and pregelatinized starch. Examples of adsorbents include, but are not limited to, aluminum hydroxide adj uvant; aluminum oxide; aluminum phosphate adj uvant; attapulgite; bentonite; powdered cellulose; colloidal silicon dioxide; hectorite; kaolin; magnesium aluminum silicate; magnesium carbonate; microcrystalline cellulose; pectin; polycarbophil; and saponite.

The following examples are provided to illustrate certain aspects of the present invention and to aid those of skilled in the art in practicing this invention. These examples are in no way to be considered to limit the scope of the invention in any manner.

Example 1. Production Methods

The formulation development studies started with the investigation of the physical properties, chemical properties, solubility and pharmacokinetic properties of the active ingredients. In this invention, the extended release (ER) Memantine HCI portion and the immediate release Donepezil HCI portion were separately produced with different processes. In order to provide extended release of memantine HCI, it is aimed to develop pellets with controlled release. Granulation methods and direct mixing were tested for immediate release Donepezil HCI.

The produced formulation contain the following inactive ingredients: povidone, talc, hypromellose, polyethylene glycol, ethylcellulose, oleic acid, medium chain triglycerides, ammonium hydroxide, lactose, microcrystalline cellulose, corn starch, colloidal silicon dioxide, and magnesium stearate. The hard gelatin capsules contain titanium dioxide, gelatin, shellac glaze, and black iron oxide; colorants are FD&C Blue 1 and yellow iron oxide.

ER portion was produced by forming a memantine pellet; then followed by coating the obtained memantine pellets with an extended release coating (i.e. , ER coating) outside each pellet. Ethylcellulose polymer is widely used in pharmaceutical coating, especially when producing modified release dosage forms. The drug release rate was controlled by determining the optimum values after different amounts of coating levels. For the immediate release donepezil portion, dry granulation showed good flowability and proper content uniformity.

The finished product was obtained by filling the obtained controlled release memantine HCI coated pellets and the obtained immediate release donepezil HCI granules into the gelatin capsules.

Example 2. Particle Size Distribution Analysis

In order to examine the effect of particle size distribution of donepezil granules and memantine pellets on the capsule filling process, the obtained granules/ pellets (Example 1) were grouped by size and capsule filling process were developed.

Donepezil granules Memantine pellet

D1 D90 < 200 pm M1 800 pm < D90 < 1200 pm

D2 200 pm < D90 < 350 pm M2 1200 pm < D90 < 1500 pm

D3 350 pm < D90 < 500 pm

D4 500 pm < D90

Capsule filling was carried out with the granules/ pellets obtained, the particle sizes of which were specified above, after filling the required amount of the first active substance for the dose, the capsule filling is continued with the required amount of the second active substance. If said first active substance is donepezil granule, said second active substance is memantine pellet, and if said first active substance is memantine pellet, said second active substance is donepezil granule.

Flowability Problem Content Uniformity Problem

D1 Yes X

D2+M1 No No

D2+M2 No No

D3+M1 No No

D3+M2 No No

D4+M1 No Yes

D4+M2 No Yes

X: Not applicable

The donepezil granules having particle size distribution smaller than 200 pm (D1) fail in capsule filling process because of the poor flowability of the obtained donepezil granules. On the other hand, the drug products of D4+M1 and D4+M2 have content uniformity problems.

The drug product compositions of D2+M1, D2+M2, D3+M1, D3+M2 have good flowability properties and consequently have proper content uniformity results of donepezil and memantine active substances. The capsules obtained with the specific particle size distribution display high content uniformity.

According to flowability and content uniformity results, tapped density and bulk density measurements were made for donepezil granules having particle size distribution 200 pm < D90 < 500 pm (D2 and D3). The Hausner-factor is the ratio of tapped density to bulk density. It is a measure of the compressibility of the respective powder. The results showed that donepezil granules should have Hausner factor below 1.5, preferably below 1.4 to provide an improved system for filling hard gelatin capsules with combined dissimilar materials in order to overcome content uniformity problems.

Example 3. Dissolution Profiles

Comparative dissolution tests were conducted based on proposed FDA dissolution methods for donepezil HCI/ Memantine HCI Extended Release Capsule. The proposed FDA dissolution method is pH 1.2 NaCI/HCI buffer (900 ml) USP App I (basket) at 100 rpm at 10, 15, 20, 30, 45 and 60 minutes for donepezil and at 1 , 2, 3, 4, 6, 8, 10 and 12 hours for memantine.

The in vitro dissolution profile of the IR/SR capsule of test product was obtained under simulated gastric condition. The dissolution tests were performed in 0.1 N HCI-pH 1.2 solution at a temperature of 37°C. Samples of dissolution media were collected at predetermined intervals and analyzed by high performance liquid chromatography (HPLC). Dissolution results of D2+M1, D2+M2, D3+M1, D3+M2 are quite similar among them and also show similar profiles with the reference product with appropriate f2 values.

Example 4. Stability Studies

The stability of a drug substance is an important factor in the manufacture of safe and effective pharmaceutical products. Stability studies are required to be submitted by any applicant seeking approval for a new pharmaceutical product. The rules in force (e.g. "Note for Guidance on Impurities in New Drug Products" CPMP/ICH/2738/99, issued by EMEA, European Medicines Agency) provide strict limitations for impurities, nevertheless it is better to prevent or reduce as possible the degradation to avoid the exposure of patients to substances.

The stability of a pharmaceutical dosage form is related to maintaining its physical, chemical, microbiological, therapeutic, and toxicological properties when stored, i.e., in a particular container and environment. Stability issues can be caused by environmental factors such as humidity, temperature and the like.

Accelerated stability tests are performed by storing a product in stress conditions. These tests allow predicting the shelf life of the product over the years when it will be stored in normal storage conditions. The accelerated stability test in this case was performed according to the EMEA Guideline on Stability Testing (CPMP/QWP/122/02, rev 1), i.e. by maintaining the product in its container at a temperature of 40°C ± 2°C and 75% ± 5 %RH (Relative Humidity) for six months.

Thus, in the development of capsule form, the applicant carried out both accelerated and ambient stability studies for the test and reference products. The accelerated stability condition is temperature of 40°C ± 2°C and 75 % ± 5°C RH for up to 6 months and ambient stability condition is temperature of 25°C±2°C and 60% ± 5% RH for up to 24 months.

Test product capsule formulations were packed in Alu-Alu containers and they were charged on to the stability cabinets. Samples were taken out at each stability stage interval and submitted for analysis. The results are summarized in the following Table 1. In addition, the present compositions and formulations display high storage stability, the long term storage stability is ascertained for 12 months at 30°C±2°C and 65% ± 5% RH and 24 months at 25°C±2°C and 60% ± 5% RH (Table 2).

Table 1. Comparative stability results (degradation products) for Test products initially and after 6 months at 40°C±2°C/ 75%±5 %RH and after 6 months at 25°C±2°C/ 60±5% Relative Humidity, RH±5% storage conditions.

Degradation Product (%)

. . . .. After 6 months After 6 months n^{itia y} (40°C±2°C, 75%RH) (25°C±2°C, 60%RH)

Donepezil Memantine Donepezil Memantine Donepezil Memantine

Total Imp. Total Imp. Total Imp. Total Imp. Total Imp. Total Imp.

Table 2. Long term stability results (degradation products) for Test products after 12 months at 30°C±2°C/ 65%±5 %RH and after 24 months at 25°C±2°C/ 60±5% Relative Humidity, RH±5% storage conditions.

Degradation Product (%)

After 12 months After 24 months

(30°C±2°C, 65%RH) (25°C±2°C, 60%RH)

Donepezil Total Memantine Donepezil Memantine

Imp. Total Imp. Total Imp. Total Imp.

Test Product <RL 0.37 0.10 0.44

* RL: Reporting limit Example 5. Bioequivalence study

As per LISFDA guideline titled "Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations" Bioequivalence is defined as: "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study."

The fixed-dose capsules produced with the present invention have been found to be bioequivalent to reference product Namzaric® with the bioequivalence study conducted in normal, healthy, adult subjects under fasting and fed conditions.

Claims

1. A pharmaceutical fixed-dose composition of donepezil or a pharmaceutically acceptable salt thereof, and memantine or a pharmaceutically acceptable salt thereof, comprising: a) immediate release donepezil HCI granules, and b) extended release memantine HCI pellets, wherein the particle size distribution of donepezil granules is 200 pm < D90 < 500 pm.

2. The pharmaceutical fixed-dose composition according to claim 1 , wherein the particle size distribution of memantine pellets is 800 pm < D90 < 1500 pm.

3. The pharmaceutical fixed-dose composition according to claim 1 , wherein the particle size distribution of donepezil granules is 250 pm < D90 < 500 pm.

4. The pharmaceutical fixed-dose composition according to claim 1 , wherein the particle size distribution of donepezil granules is 250 pm < D90 < 400 pm.

5. The pharmaceutical fixed-dose composition according to claim 2, wherein the particle size distribution of memantine pellets is 900 pm < D90 < 1400 pm.

6. The pharmaceutical fixed-dose composition according to claim 2, wherein the particle size distribution of memantine pellets is 1000 pm < D90 < 1400 pm.

7. The pharmaceutical fixed-dose composition according to claim 1 , wherein the Hausner factor of donepezil granules is below 1.5, preferably below 1.4.

8. The pharmaceutical fixed-dose composition according to claim 1 , wherein the said composition is capsule.

9. The pharmaceutical fixed-dose composition according to claim 1 , wherein the said composition comprises at least one pharmaceutically acceptable excipient.

10. The pharmaceutical fixed-dose composition according to claim 9, wherein the said composition comprises povidone, talc, hypromellose, polyethylene glycol, ethylcellulose, oleic acid, medium chain triglycerides, ammonium hydroxide, lactose, microcrystalline cellulose, corn starch, colloidal silicon dioxide, and magnesium stearate.

11. The pharmaceutical fixed-dose composition according to claim 9, wherein the said composition is used for the disorder related to central nervous system (CNS), Alzheimer’s disease.