RS64694B1 - Immediate release fixed-dose combination of memantine and donepezil - Google Patents

Description

Description

FIELD OF INVENTION

The present invention relates to a fixed-dose immediate-release combined pharmaceutical composition containing donepezil and memantine for the treatment of Alzheimer's disease.

STATE OF THE ART

According to the United States Pharmacopeia (USP), immediate-release solid oral formulations containing donepezil hydrochloride or memantine hydrochloride refer to formulations that exhibit at least 80% solubility of the drug within 30 minutes in 0.1 N hydrochloric acid.

Donepezil is the International Nonproprietary Name (INN) for (RS)-2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one, which has the following chemical structure:

Memantine is the INN for 3,5-dimethyladamantan-1-amine, which has the following chemical structure:

Donepezil is an acetylcholinesterase inhibitor. Pharmaceutical formulations of donepezil in the form of the hydrochloride salt are registered and marketed under the trade name ARICEPT<®>for the treatment of mild to moderately severe Alzheimer's dementia.

Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist. Pharmaceutical compositions of memantine in the form of the hydrochloride salt are registered and marketed under the trade name EBIXA<®>for the treatment of moderate to severe Alzheimer's disease.

WO 03/101458 discloses pharmaceutical compositions containing acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. However, no specific pharmaceutical formulation of donepezil or memantine has been submitted for review. Furthermore, no fixed-dose composition was examined.

Document WO 2004/037234 discloses combination therapy using 1-aminocyclohexane derivatives such as memantine or neramexane, together with acetylcholinesterase inhibitors (AChEIs) such as galantamine, tacrine, donepezil or rivastigmine, for the treatment of dementia by inducing cognitive improvements. No specific pharmaceutical formulations of donepezil or memantine, or any fixed-dose formulations, were reviewed. It is clear from the example that the active ingredients are provided in separate units.

Document WO 2006/121560 discloses fixed-dose pharmaceutical compositions of donepezil and memantine, wherein one or both agents are provided in a sustained-release dosage form, i.e. with an in vitro dissolution profile of less than 70% over one hour, using a USP type 2 (scoop) dissolution system at 50 rpm, at a temperature of 37°C with water as the dissolution medium.

WO 2018/062941 discloses an immediate release combination in the form of a direct compressed (oral) tablet containing memantine and wet granulated donepezil. Said formulation includes 10 mg donepezil HCl and 20 mg memantine HCl; it is intended to be used to treat moderate Alzheimer's disease. The mentioned formulation contains lactose and microcrystalline cellulose.

There is no guidance in the prior art on how to design, develop and manufacture fixed-dose oral pharmaceutical compositions containing immediate release memantine and donepezil for the treatment or therapy of moderate to severe Alzheimer's disease. In particular, there is no guidance on how to design, develop and manufacture a given pharmaceutical composition so that it simultaneously exhibits a number of characteristics that can make the same compositions suitable for production on a commercial scale.

There are several obstacles that inventors must overcome during the development of a fixed-dose combination product containing the active ingredients donepezil and memantine. The inventors of the subject application faced unconventional challenges that required a significant amount of research activity in order to develop a fixed-dose combination pharmaceutical composition suitable for commercial production. Specifically, a composition that simultaneously exhibits appropriate stability, cost-effectiveness and robustness of the process (good uniformity, good fluidity, good compactness/compressibility, mass uniformity and adequate hardness). At the same time, the new fixed-dose combination formulation must show pharmacokinetics comparable to products containing either donepezil or memantine alone, which are currently available on the market.

Current formulations of donepezil (ARICEPT<®>) and memantine (EBIXA<®>) on the market have different formulations and use different excipients. This shows that it is possible to produce compositions of donepezil and memantine using different techniques.

In the design of fixed-dose combination pharmaceutical compositions, direct approaches such as just combining excipients in an additive manner are undeniably rare or even non-existent. If one skilled in the art were tasked with developing a fixed-dose combination formulation that is bioequivalent to the monoproducts, the obvious course of action would be to include, as far as possible, all of the ingredients present in both monoproducts. However, the above-mentioned procedure lacks any practical applicability, because the selected excipients must have a very clear function. That is, a certain excipient should be chosen for a certain specific effect. The presence of a certain excipient should be proven to produce the desired effect. Commercially available monoproducts, their composition and their excipients are listed in Table 1 according to their respective Summary of Product Characteristics (SmPC).

Table 1 - commercially available monoproducts, their composition and their excipients are listed in Table 1 according to their Summary of Product Characteristics.

Analyzing the compositions described for commercial monoproducts, it becomes apparent that simply adding the compositions together is not a rational or practical approach for developing a fixed-dose combination composition.

A person skilled in the art is aware of the suitability of a particular excipient for a specific manufacturing process. Additionally, given the very poor fluidity and compaction properties of memantine and donepezil, the current approach will be to process the powder using high-shear granulation, followed by the necessary downstream steps to convert the granulated material into a solid form for oral dosage. Once it is judged that a wet granulation process is required, one skilled in the art will use a variety of excipients to improve processability. The combination of lactose monohydrate with microcrystalline cellulose in solid oral dosage forms is a common practice. When properly formulated, the fragmentation properties of lactose monohydrate, combined with the highly plastic behavior of microcrystalline cellulose, provide tablets with high mechanical strength; a required property so that the tablets can withstand further processing and manipulation (ie dust removal, transport, film coating and/or packaging). As a result of the required manufacturing process, the simplest approach to develop a fixed-dose combination of donepezil and memantine will be to associate the excipients present in Aricept<®> with both drug compositions.

Memantine is not compatible with some excipients present in ARICEPT<®>. In particular, Memantine is not compatible with lactose, which is present in the formulation of ARICEPT<®>. It is known that memantine and lactose can form a memantine-lactose adduct (MLA), through the Maillard reaction (an API containing an amine group, such as memantine, has been described to react with carbohydrates via the Maillard reaction to give carbohydrate-conjugated adducts). The presence of MLA was confirmed in formulations containing lactose and memantine, where significant amounts of MLA were formed after subjecting the formulated product to stress stability studies.

By reducing the amount of lactose in the formulation, it is expected that the amount of MLA will also be reduced. Lactose reduction must be compensated by alternative excipients that have similar function/properties to lactose. However, there is no unique excipient completely similar (biological, chemical and physical properties) to lactose that could replace lactose monohydrate.

Even if one is directed to use polyols (mannitol, xylitol, maltitol, etc.) as excipients, since these excipients possess solubility and compaction properties equivalent to those of lactose, such direction is likely to be rejected by the skilled person. One skilled in the art is one who is aware of two major negative factors known in the art.

First, these classes of excipients have a detrimental effect on small intestinal transit time, and consequently affect drug absorption (Guideline for Bioequivalence Testing - CPMP/EWP/QWP/1401/98 Rev. 1/ Corr).

Contrary to all expectations of the expert, it is possible to obtain an immediate release oral pharmaceutical composition that meets all requirements and can be adapted for robust production. In particular, it is possible to create a fixed-dose, immediate-release combination composition that, when ingested, does not produce MLA and has in vivo stability and bioequivalence that is similar to a composition containing donepezil or memantine as the sole active ingredient (namely, the current commercial monoproducts).

These facts are made available to the public to illustrate the technical problem addressed by the present invention.

GENERAL DESCRIPTION

The present invention relates to a fixed-dose, immediate-release combined pharmaceutical composition containing the active pharmaceutical ingredients (API) donepezil and memantine, for the treatment of moderate to severe Alzheimer's disease.

The invention is defined by the patent claims. Any subject matter not falling within the scope of the patent claims is provided for informational purposes only.

An aspect of the present invention is the use of a composition of the present invention in the treatment or therapy of moderate to severe Alzheimer's disease.

Another aspect of the present invention is a fixed-dose, immediate-release pharmaceutical composition for oral use, for use in the treatment or therapy of moderate to severe Alzheimer's disease, comprising:

from 4.16 mg to 20 mg of memantine or a pharmaceutically acceptable salt; and

from 4.56 mg to 10 mg of donepezil or a pharmaceutically acceptable salt;

whereby memantine or a pharmaceutically acceptable salt and donepezil or a pharmaceutically acceptable salt are the only active substances;

45.0 wt. % to 60.0 wt. % mannitol;

wherein the pharmaceutical composition is lactose-free;

and less than 1.0% by weight of reducing sugars relative to the total weight of the composition.

The fixed-dose immediate-release combined pharmaceutical composition for oral use of the present invention has a dissolution rate of memantine and donepezil in a pH 1 solubility test solution that is greater than 90% within 5 minutes.

The composition of the present invention surprisingly provides improved dissolution rate, adequate disintegration rate and better shelf stability.

In one embodiment, for better results, the dissolution rate of memantine and donepezil in the pH 1 solubility test solution is greater than 91% within 5 minutes; preferably more than 92% within 5 minutes, preferably more than 93% within 5 minutes, preferably more than 94% within 5 minutes; preferably more than 95% within 5 minutes.

The disintegration test is intended to determine whether tablets, capsules or granules disintegrate within a prescribed time when placed in a liquid medium under experimental conditions. The experimental procedure and requirements for disintegration differ depending on the group of pharmaceutical forms: uncoated or coated tablets; delayed-release tablets and capsules (ie, tablets or capsules that are formulated with an acid-resistant coating or an enteric coating); buccal tablets, sublingual tablets, tablets for oral suspension, tablets for oral solution, orally dispersible tablets (ODT) and chewable tablets; effervescent tablets or granules. For orally disintegrating tablets, the term 'in vitro disintegration time' means that the tablet disintegrates in the oral cavity mainly in a saliva disintegration test or a device disintegration test, usually in 5 to 120 seconds, preferably in 5 to 60 seconds, more preferably in about 5 to 40 seconds, using water at 15-25 °C as the liquid medium. The disintegration test of coated or uncoated tablets is performed using water at 37°C for a maximum of 15 minutes.

In one embodiment, for better results, the composition is bioequivalent and the bioequivalence of the composition is given with a 90% confidence interval (CI) for the ratio of geometric means AUC for donepezil and memantine in plasma of 80.00 to 125.00%, and with a 90% Cl for the ratio of geometric means Cmax for donepezil and memantine in plasma of 80.00 to 125.00%. Preferably, the bioequivalence of the composition is given by a 90% Cl for a ratio of geometric means AUC for donepezil to memantine in plasma of 90.00 to 111.00%, and a 90% Cl for a ratio of geometric means Cmax for donepezil to memantine in plasma of 90.00 to 111.00%.

In one embodiment, for better results, the evaluation points for the log transformed ratios of AUC and Cmax for donepezil and memantine plasma concentrations are from 95.00% to 105.00%.

In one embodiment, for better results, the composition is bioequivalent and the bioequivalence of the composition is given by a 90% Cl (confidence interval) for the ratio of geometric means AUC for donepezil and memantine in plasma of 80.00 to 125.00% and, with a 90% Cl for the ratio of geometric means Cmax for donepezil and memantine in plasma of 80.00 to 125.00%, with point estimates of 95.00 to 105.00%.

In one embodiment, for better results, the composition is bioequivalent and the bioequivalence of the composition is given by a 90% Cl for the ratio of geometric means AUC for donepezil and memantine in plasma of 90.00 to 111.00%, and with a 90% Cl for the ratio of geometric means Cmax for donepezil and memantine in plasma of 90.00 to 111.00%, with point estimates of 95.00 to 105.00%.

In one embodiment, for better results, the bioequivalence of memantine in the composition is equivalent to EBIXA<®> and the bioequivalence of donepezil in the composition is equivalent to ARICEPT<®>.

In one embodiment, for better results, the composition of the subject invention may contain 45.0 wt. % to 60.0 wt. % mannitol, preferably from 45.0 wt. % to 55.0 wt. % mannitol.

In one embodiment, for better results, the composition of the present invention can be dissolved in more than or equal to 2 min, using water at 37°C as the liquid medium.

In one embodiment, for better results, the pharmaceutically acceptable salt of memantine is memantine hydrochloride, preferably in amounts of 5 mg to 20 mg per dose.

In one embodiment, for better results, a pharmaceutically acceptable salt of donepezil is donepezil hydrochloride, preferably in amounts of 5 mg to 10 mg per dose.

In one embodiment, for better results, the composition of the present invention may contain less than 1.0% by weight of reducing sugars relative to the total weight of the composition, preferably less than 0.6% by weight, more preferably less than 0.4% by weight, most preferably less than 0.3% by weight.

In one embodiment, for better results, the dissolution rate of memantine and donepezil in the solubility test solution at pH 1 is greater than 92% within 5 minutes, preferably greater than 93% within 5 minutes, most preferably greater than 95% within 5 minutes.

In one embodiment, for better results, the composition of the subject invention may contain less than 2.5 wt. % of memantine-lactose adduct (MLA) in relation to the weight of memantine, preferably less than 1.4 wt. %, preferably less than 1.0 wt. %.

In one embodiment, for better results, the composition of the subject invention may further contain:

one or more disintegrants;

one or more binders;

one or more diluents;

one or more lubricants;

optionally one or more sliding means;

other pharmaceutically acceptable excipients.

In one embodiment, for better results, the composition of the subject invention may contain from 2 wt.% to 30 wt.% of one or more disintegrants;

from 0.5 wt.% to 10 wt.% of one or more binders;

from 5 wt.% to 80 wt.% of one or more diluents;

from 0.1 wt.% to 5 wt.% of one or more lubricants.

[0045] In one embodiment, for better results, the composition of the present invention may contain one or more disintegrants selected from the list consisting of: starch, carboxymethyl cellulose (carmellose), cross-linked carboxymethyl cellulose (croscarmellose), sodium starch glycolate, low substituted hydroxypropyl cellulose (L-HPC), carboxymethyl starch, polyvinylpyrrolidone, crospovidone and their mixtures;

one or more binders selected from the list consisting of: hydroxypropyl cellulose (HPC), low substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl methylcellulose (HPMC), methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polyethylene glycol, maltodextrin, pregelatinized starch, polymethacrylates, sodium alginate, polyvinylpyrrolidone (povidone), vinylpyrrolidone/vinylacetate copolymer (copovidone) and their mixtures;

one or more diluents selected from the list consisting of: microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), sorbitol, lactitol, xylitol, isomalt, dextrin, and mixtures thereof; preferably microcrystalline cellulose;

one or more lubricants selected from the list consisting of: magnesium stearate, calcium stearate, sodium stearate, stearic acid, sodium glyceryl behenate, sodium stearyl fumarate and mixtures thereof.

In one embodiment, for better results, the composition of the subject invention may contain:

of 5 wt. % up to 25 wt. % corn starch;

of 5 wt. % up to 20 wt. % croscarmellose sodium;

of 1 wt. % to 4 wt. % hydroxypropyl cellulose (HPC);

of 45.0 wt. % up to 60 wt. % mannitol;

of 5 wt. % up to 20 wt. % microcrystalline cellulose;

of 0.1 wt. % to 5 wt. % magnesium stearate;

where all are heavier. % in relation to the total weight of the composition.

In one embodiment, for better results, the composition of the subject invention can be obtained by wet granulation.

Another aspect of the present invention relates to a process for producing a fixed-dose, immediate-release pharmaceutical composition for oral use according to the present invention, comprising the steps of:

preparation of a homogeneous mixture containing

donepezil or a pharmaceutically acceptable salt, especially donepezil hydrochloride, memantine or a pharmaceutically acceptable salt, especially memantine hydrochloride, 45.0 wt. % to 60.0 wt. % mannitol;

one or more disintegrants, one or more binders and one or more diluents; obtaining granules by wet granulation;

drying of wet granules and sieving;

mixing granules with one or more lubricants;

compressing the final mixture into a tablet;

optional coating of the tablet with a film.

BRIEF DESCRIPTION OF THE DRAWINGS

The following figures provide preferred embodiments for illustrating the invention and should not be considered limiting of the scope of the invention.

Figure 1 shows the XRPD of donepezil hydrochloride form I.

Figure 2 shows the XRPD of memantine hydrochloride form I.

Figure 3 shows the dissolution profiles of donepezil hydrochloride released from formulations according to Example 1 of the present invention.

Figure 4 shows the dissolution profiles of memantine hydrochloride released from the formulations according to Example 1 of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a fixed-dose immediate-release combined pharmaceutical composition containing the active pharmaceutical ingredients (API) memantine and donepezil for the treatment of moderate to severe Alzheimer's disease.

In a preferred embodiment, memantine and donepezil are used in the form of their hydrochloride salts, ie. as memantine hydrochloride (memantine HCl) and donepezil hydrochloride (donepezil HCl).

In a more preferred embodiment, memantine HCl is used in crystalline Form I according to WO 2006/076560 and donepezil HCl is used in crystalline Form I according to US 6,140,321.

Memantine can be produced according to methods known in the art, e.g. as disclosed to the public in document EP 0392 059. Memantine HCl in crystalline Form I can be produced in accordance with document WO 2006/076560.

Donepezil can be produced according to methods known in the art, e.g. as disclosed in EP 0296 560. Donepezil HCl in crystalline Form I can be produced in accordance with US 6,140,321.

The dissolution rate of the immediate release fixed dose oral memantine and donepezil combined pharmaceutical composition is greater than 70% within 5 minutes, more preferably greater than 75% within 5 minutes, most preferably greater than 80% within 5 minutes.

In one embodiment, the memantine and donepezil fixed-dose combination pharmaceutical composition for immediate release oral use comprises 4.56 mg to 9.12 mg of donepezil. In another embodiment, donepezil HCl is present in amounts ranging from 5 mg to 10 mg per unit (dose).

In another embodiment, the memantine and donepezil fixed dose immediate release oral pharmaceutical composition comprises 4.16 mg to 16.62 mg of memantine. In yet another embodiment, memantine HCl is present in amounts ranging from 5 mg to 20 mg per unit (dose).

In one embodiment, the immediate release fixed dose oral pharmaceutical composition of the present invention is lactose free.

In one aspect of the present invention, the immediate-release oral fixed-dose combination pharmaceutical composition has a donepezil release profile that results in a 90% confidence interval (90% Cl) for the ratio of the geometric means of the AUC (area under the plasma concentration-time curve) for the test product (subject invention) and Aricept<®> (reference product) of 80.00 to 125.00%, preferably from 90.00 to 111.00%.

In another aspect of the invention, the immediate-release oral fixed-dose combination pharmaceutical composition has a release profile for donepezil that results in a 90% Cl for the ratio of the geometric mean Cmax (maximum plasma concentration) for the test product (subject invention) and Aricept<®> (reference product), from 80.00 to 125.00%, more preferably from 90.00 to 111.00%.

In another aspect of the present invention, the immediate-release oral fixed-dose combination pharmaceutical composition has a release profile for memantine resulting in a 90% Cl for the ratio of the geometric mean AUC (area under the plasma concentration versus time curve) for the test product (subject invention) and Ebixa<®> (reference product), from 80.00 to 125.00%, more preferably from 90.00 up to 111.00%.

In a further aspect of the present invention, the immediate-release oral fixed-dose combination pharmaceutical composition has a release profile for memantine that results in a 90% confidence interval (90% Cl) for the ratio of the geometric mean Cmax (maximum plasma concentration) for the test product (subject invention) and Ebixa<®> (reference product) of 80.00 to 125.00%, preferably from 90.00 to 111.00%.

In one embodiment, in addition to the combination of donepezil and memantine, the pharmaceutical compositions according to the present invention may further contain one or more disintegrants, one or more binders, one or more diluents, one or more lubricants, one or more glidants and optionally one or more other pharmaceutically acceptable excipients. In the context of the present invention, the terms active, disintegrant(s), binder(s), diluent(s), lubricant(s), glidant(s), etc., should be understood to include a single compound, but also multiple compounds.

In one embodiment, pharmaceutically acceptable disintegrants include, but are not limited to starch, carboxymethyl cellulose (carmellose), cross-linked carboxymethyl cellulose (croscarmellose), sodium starch glycolate, low substituted hydroxypropyl cellulose (L-HPC), carboxymethyl starch, polyvinylpyrrolidone, crospovidone, and mixtures thereof. Preferably, the pharmaceutical composition contains from 2 wt. % up to 30 wt. % corn starch and/or croscarmellose sodium disintegrants. In particularly preferred embodiments, the pharmaceutical composition contains from 5 wt. % up to 25 wt. % corn starch and from 5 wt. % to 20 wt. % croscarmellose sodium.

In one embodiment, the pharmaceutically acceptable binder(s) include, but are not limited to, hydroxypropyl cellulose (HPC), low substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl methylcellulose (HPMC), methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polyethylene glycol, maltodextrin, pregelatinized starch, polymethacrylates, sodium alginate, polyvinylpyrrolidone (povidone), vinylpyrrolidone/vinyl acetate copolymer. (copovidone) and their mixtures. The preferred binder is hydroxypropyl cellulose (HPC).

In a preferred embodiment, the amount of one or more binders is 0.5 wt. % to 10 wt. %, more preferably than 1 wt. % to 5 wt. %. In a particularly preferred embodiment, the pharmaceutical composition of the present invention contains from 1 wt. % to 4 wt. % hydroxypropyl cellulose (HPC).

In one embodiment, the pharmaceutically acceptable diluent(s) include, but are not limited to, microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), mannitol, sorbitol, lactitol, xylitol, isomalt, dextrin, and mixtures thereof. Preferably, the pharmaceutical composition of the present invention contains from 5.0 wt. % to 80.0 wt. % of one or more diluents.

In one embodiment, the pharmaceutical composition of the present invention contains from 5 wt. % up to 20 wt. % of microcrystalline cellulose in relation to the total weight of the composition. In one embodiment, the pharmaceutical composition of the subject invention contains 45.0 wt. % to 60.0 wt. % mannitol, preferably from 45.0 wt. % up to 55 wt. % of mannitol in relation to the total weight of the composition.

In one embodiment, preferred diluents are mannitol, microcrystalline cellulose (MCC), and mixtures thereof. In the pharmaceutical compositions of the subject invention, the sum of the amount of pharmaceutically active ingredients and the amount of diluent (microcrystalline cellulose and mannitol) is from 190 mg to 210 mg. Further, the sum of the amount of memantine or its pharmaceutically acceptable salt and the amount of diluent (microcrystalline cellulose and mannitol) is from 180 mg to 200 mg.

In one embodiment, suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, sodium stearate, stearic acid, sodium glyceryl behenate, sodium stearyl fumarate, and mixtures thereof. Preferably, the pharmaceutical composition of the present invention contains from 0.1 wt. % to 5 wt. % of one or more lubricants. In a particularly preferred embodiment, the pharmaceutical composition of the present invention contains from 0.1 wt. % to 5 wt. % of magnesium stearate in relation to the total weight of the composition.

In one embodiment, the pharmaceutical composition of the present invention optionally contains pharmaceutically acceptable glidants such as colloidal silicon dioxide, talc, magnesium carbonate, and mixtures thereof. The amount of glidants is preferably 0.1 wt. % to 1.5 wt. %, in relation to the total weight of the composition.

Another aspect of the present invention relates to processes for the manufacture of a fixed dose immediate release pharmaceutical composition for oral use.

In one embodiment, the process of preparing the pharmaceutical composition of the present invention includes a) mixing pharmaceutically effective amounts of donepezil and memantine, or their pharmaceutically acceptable salts, with at least one diluent, optionally one or more binders and optionally one or more disintegrants; b) adding a lubricant, and optionally one or more pharmaceutically acceptable excipients, and mixing the compositions together; c) compressing the final mixture into a larger number of tablets; d) optional tablet coating.

In another embodiment, the process of preparing the pharmaceutical composition of the subject invention includes a) mixing pharmaceutically effective amounts of donepezil and memantine, or their pharmaceutically acceptable salts, with at least one diluent, optionally one or more binders and, optionally, one or more disintegrants; b) granulating the previous mixture, in a manner known in the art, in order to obtain a larger number of granules; c) mixing the granules with a lubricant, and optionally with one or more pharmaceutically acceptable excipients; d) compressing the final mixture into a larger number of tablets; e) optional tablet coating.

In one embodiment, the mixing step prior to granulation is performed in a diffusion mixer, high shear granulator, or fluidized bed dryer, preferably in a high shear mixer in a manner known in the art. When wet granulation is used to prepare the granules, the resulting granules are dried before the next steps. Optionally, wet granules may require an intermediate step of wet grinding, prior to drying, through a relatively coarse mesh to break up oversized agglomerates and promote a faster drying process. The granules can be dried, for example, in a fluidized bed dryer or in a static bed oven. Preferably, the granules are dried in a fluidized bed dryer. Optionally, the dried granules are ground in a suitable mill. Preferred mills are impact mills, cutting mills or screening mills. It is most preferable to use a sifting mill. The tablets are preferably coated in a manner known to a person skilled in the art. It is desirable that the coating contains color pigments.

EXAMPLES

EXAMPLE 1 - Qualitative and quantitative composition of combined compositions with a fixed dose without lactose in accordance with the present invention

Table 2 - Donepezil HCl Memantine HCl tablets according to the present invention

The pharmaceutical compositions from example 1 were prepared by a conventional wet granulation technique that includes the following steps: a) mixing donepezil HCl and memantine HCl, mannitol, microcrystalline cellulose, corn starch, hydroxypropyl cellulose and croscarmellose; b) granulating the mixture with water to obtain a wet mass; c) optional grinding of wet mass c) drying of wet mass; e) grinding of dried granules; f) mixing dried granules with lubricant; f) compressing the lubricated mixture into a larger number of tablets; d) optionally, coating the tablet by a process well known in the art.

REFERENCE EXAMPLE (R1)

Formulations containing lactose were produced according to the steps described in Example 1. In Example R1, mannitol was replaced by lactose.

The resulting tablets were incubated in an oven at 60°C. After a predetermined time, the samples were tested for memantine-lactose adduct (MLA). The results (%) are summarized in the table below.

The sum of the amount of pharmaceutical active ingredients and the amount of diluent (microcrystalline cellulose and lactose monohydrate) is from 190 mg to 210 mg. Furthermore, the sum of the amount of memantine or its pharmaceutically acceptable salt and the amount of diluent (microcrystalline cellulose and lactose monohydrate) is from 180 mg to 200 mg.

Table 3 - Donepezil HCl Memantine HCl tablets reference example

Table 4 - Stability of formulations containing lactose

Table 5 - Stability of formulations containing lactose

Notably, these experiments show that the lower the amount of lactose in the fixed dose composition, the higher the amount of memantine-lactose adduct (MLA) impurity.

When lactose was replaced by mannitol, surprisingly no memantine-lactose adduct (MLA) impurity was detected (Table 6). As such, the composition of the present invention is more stable.

Table 6 - Content of memantine-lactose adduct (MLA)

Dissolution testing

The in vitro dissolution of the tablets of EXAMPLE 1 containing donepezil HCl and memantine HCl was determined according to the procedure described in Table 7.

Table 7 - Tablet dissolution parameters in vitro

Table 8 - Memantine dissolution data (%) for tablets of Example 1

Table 9 - Donepezil dissolution data (%) of Example 1 tablets

Table 10 - Data on the dissolution of memantine and donepezil (%) for tablets of the reference example (lactose ratio: memantine HCl = 7.38)

Table 11 - Data related to the bioequivalence of the composition of the subject invention with EBIXA<®> and with ARICEPT<®>

It is well known in the scientific community that mannitol can hinder the adsorption of APIs, it is actually described in the Guidelines for Bioequivalence Testing (CPMP/EWP/QWP/1401/98 Rev.1/ Corr) that mannitol can affect the gastrointestinal transit and thus the bioavailability of the drug.

Table 12 - Data related to dissolution and composition stability after 5 On release 40°C / 75% RH - 6 months

minute

% Donepezil Memantine Total Total Total Total (wt/wt Impurities Impurities Impurities Impurities Mannitol Donepezil Memantine Donepezil Memantine (%) (NMT (%) (NMT (%) (NMT (%) (NMT 2.0%) 3.0%) 2.0%)

54.1 99 0.05 0.19 <0.05

52.2 91 <0.05 <0.1 <0.05

50.4 93 <0.05 0.12 <0.05

48.5 92 <0.05 0.13 <0.05

Surprisingly, in the presence of mannitol, donepezil and memantine were shown to be bioequivalent to the monoproducts, which allowed the conclusion that mannitol does not affect the bioavailability of both substances when formulated as a fixed-dose, immediate-release formulation. The composition of the present invention does not produce different levels of absorption compared to products containing only memantine or only donepezil.

The results show that the surprising composition of the present invention provides improved dissolution rate, improved disintegration rate and improved shelf stability.

Accordingly, preferred embodiments of the present invention relate to immediate release oral pharmaceutical compositions that are bioequivalent compared to memantine alone (namely, the EBIXA<®> reference product) and compared to donepezil alone (namely, the ARICEPT<®> reference product).

Where ranges are given, endpoints are included.

Claims (11)

Patent claims 1. An oral fixed dose immediate release pharmaceutical composition for use in the treatment or therapy of moderate to severe Alzheimer's disease, comprising: from 4.16 mg to 20 mg of memantine or a pharmaceutically acceptable salt; and from 4.56 mg to 10 mg of donepezil or a pharmaceutically acceptable salt; whereby memantine or a pharmaceutically acceptable salt and donepezil or a pharmaceutically acceptable salt are the only active substances; 45.0 wt. % to 60.0 wt. % mannitol; wherein the pharmaceutical composition is lactose-free; and less than 1.0% by weight of reducing sugars relative to the total weight of the composition. 2. The composition for use according to the previous claim, which contains from 45.0 wt. % to 55.0 wt. % mannitol. 3. A composition for use according to the preceding claims containing less than 0.6 wt.% of reducing sugars relative to the total weight of the composition, preferably less than 0.4 wt.%. 4. A composition for use according to the preceding claims containing less than 0.3% by weight of reducing sugars. 5. The composition for use according to any of the preceding claims, wherein the pharmaceutically acceptable salt of memantine is memantine hydrochloride, preferably in amounts of 5 mg to 20 mg per dose. 6. The composition for use according to any of the preceding claims, wherein the pharmaceutically acceptable salt of donepezil is donepezil hydrochloride, preferably in amounts of 5 mg to 10 mg per dose. 7. A composition for use according to any of the preceding claims, containing less than 2.5 wt. % of memantine-lactose adduct (MLA) in relation to the weight of memantine, preferably less than 1.4 wt. %, preferably less than 1.0 wt. %. 8. A composition for use according to any of the preceding claims, further comprising: one or more disintegrants; one or more binders; one or more diluents; one or more lubricants; optionally one or more sliding means; other pharmaceutically acceptable excipients. 9. Composition for use according to any of the preceding claims, wherein the composition contains one or more disintegrants selected from the list consisting of: starch, carboxymethyl cellulose (carmellose), cross-linked carboxymethyl cellulose (croscarmellose), sodium starch glycolate, low substituted hydroxypropyl cellulose (L-HPC), carboxymethyl starch, polyvinylpyrrolidone, crospovidone and their mixtures; one or more binders selected from the list consisting of: hydroxypropyl cellulose (HPC), low substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl methylcellulose (HPMC), methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polyethylene glycol maltodextrin, pregelatinized starch, polymethacrylates, sodium alginate, polyvinylpyrrolidone (povidone), vinylpyrrolidone/vinylacetate copolymer (copovidone) and their mixtures; one or more diluents selected from the list consisting of: microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), sorbitol, lactitol, xylitol, isomalt, dextrin, and mixtures thereof; preferably microcrystalline cellulose; one or more lubricants selected from the list consisting of: magnesium stearate, calcium stearate, sodium stearate, stearic acid, sodium glyceryl behenate, sodium stearyl fumarate and mixtures thereof. 10. The composition for use according to any of the preceding claims, wherein the composition can be obtained by wet granulation. 11. A method for the production of a pharmaceutical composition according to any one of claims 1 to 10, which includes the steps: preparation of a homogeneous mixture containing donepezil or a pharmaceutically acceptable salt, especially donepezil hydrochloride, memantine or a pharmaceutically acceptable salt, especially memantine hydrochloride, 45.0 wt. % to 60.0 wt. % mannitol; one or more disintegrants, one or more binders and one or more diluents; obtaining granules by wet granulation; drying of wet granules and sieving; mixing granules with one or more lubricants; compressing the final mixture into a tablet; optional coating of the tablet with a film.