ES2960207T3 - Memantine and Donepezil Immediate-Release Fixed-Dose Combination - Google Patents

Abstract

The present disclosure relates to an immediate release fixed dose combination pharmaceutical composition comprising the active pharmaceutical ingredients Memantine and Donepezil for the treatment of moderate to severe Alzheimer's disease. (Automatic translation with Google Translate, without legal value)

Description

DESCRIPTION

Memantine and Donepezil Immediate-Release Fixed-Dose Combination

The present disclosure relates to an immediate release fixed dose combination pharmaceutical composition comprising donepezil and memantine for the treatment of Alzheimer's disease.

BACKGROUND

According to the United States Pharmacopeia (USP), immediate-release solid oral formulations containing donepezil hydrochloride or memantine hydrochloride refer to formulations that exhibit no less than 80% drug dissolution within 30 minutes in acid. hydrochloric 0.1 N.

Donepezil is the international non-proprietary name (INN) for (RS)-2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one which has the following structure chemistry:

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

Donepezil is an acetylcholinesterase inhibitor. Pharmaceutical compositions of donepezil in its hydrochloride salt form 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 its hydrochloride salt form 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 comprising acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. However, no specific pharmaceutical formulation of donepezil or memantine is disclosed. Furthermore, no fixed dose composition is disclosed.

WO 2004/037234 discloses a combination therapy using 1-aminocyclohexane derivatives such as memantine or neramexane, together with acetylcholinesterase inhibitors (AChEI) such as galantamine, tacrine, donepezil or rivastigmine, to treat dementia by inducing cognitive improvements. No specific pharmaceutical formulations of donepezil or memantine, nor any fixed dose compositions, are disclosed. From the examples it is clear that the active ingredients are provided in separate units.

WO 2006/121560 discloses fixed dose pharmaceutical compositions of donepezil and memantine in which one or both agents are provided in a sustained release dosage form, that is, with an in vitro dissolution profile of less than 70% in a hour, using a USP Type 2 dissolution system (paddles) at 50 rpm, at a temperature of 37°C with water as dissolution medium.

WO/2018/062941 discloses an immediate release combination in the form of a directly pressed (oral) tablet comprising memantine and wet granulated donepezil. Said formulation includes 10 mg of donepezil HCl and 20 mg of memantine HCl; It will be used for the treatment of moderate Alzheimer's disease. Said formulation comprises lactose and microcrystalline cellulose.

There is no guidance in the prior art on how to design, develop and manufacture oral fixed dose 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 guide on how to design, develop and manufacture said pharmaceutical composition so that it simultaneously presents a plurality of characteristics that could make the same compositions susceptible to manufacture on a commercial scale.

There are several obstacles that the inventors need to overcome during the development of a fixed-dose combination product comprising the active ingredients donepezil and memantine. The inventors of the present application faced unconventional challenges that required a substantial amount of research activities to develop a fixed-dose combination pharmaceutical composition that can be amenable to commercial scale manufacturing. Specifically, a composition that simultaneously exhibits adequate stability, cost effectiveness and process robustness (good uniformity, good fluidity, good compactibility/compressibility, mass uniformity and adequate hardness). At the same time, the novel fixed-dose combination composition should present pharmacokinetics comparable to products containing only either donepezil or memantine that are currently available on the market.

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

In the design of fixed-dose combination pharmaceutical compositions, direct approaches, such as simply combining excipients in an additive manner, are undeniably rare or even non-existent. If one skilled in the art were to be tasked with developing a fixed-dose combination composition that is bioequivalent to mono-products, the obvious method would be to include, whenever possible, all ingredients present in both mono-products. However, the aforementioned method lacks any practical applicability since the excipients chosen must have a very clear function. That is, a particular excipient must be chosen for a particular specific effect. It must be demonstrated that the presence of a particular excipient exerts the required effect. The commercially available mono-products, their composition and excipients are listed in Table 1 according to their respective summary of product characteristics (SmPC).

Table 1 - Commercially available mono-products, their composition and excipients are listed in Table 1 according to their respective summary of product characteristics.

When analyzing the compositions described for the commercial mono-products, it is evident that simply adding the compositions together is not a rational or practical approach to developing a combination composition at fixed doses of the compositions.

The person skilled in the art is aware of the suitability of a particular excipient for a specific manufacturing process. Furthermore, taking into account the very poor flow and compaction properties of memantine and donepezil, the immediate focus will be to process the powders by means of high shear granulation, followed by the subsequent steps required to convert the granulated material into a dosage form. solid oral. Once a wet granulation process is deemed necessary, one skilled in the art will use a plurality of excipients to enhance processability. The combination of lactose monohydrate with microcrystalline cellulose in solid oral dosage forms is common practice. When appropriately formulated, the fragmentation properties of lactose monohydrate, in combination with the highly plastic behavior of microcrystalline cellulose, provide tablets of high mechanical strength; a mandatory property so that the tablets can withstand subsequent processing and handling (i.e., powder extraction, transportation, film coating and/or packaging). As a result of the required manufacturing procedure, the most direct approach to developing 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 ARICEPT® formulation. It is known that memantine and lactose can form a memantine-lactose adduct (MLA), through a Maillard reaction (an API containing an amine group, such as memantine, has been described to react with a hydrate of carbon via a Maillard reaction to provide conjugated carbohydrate adducts). The presence of MLA was confirmed in formulations comprising lactose and memantine, in which substantial amounts of MLA were formed after subjecting the formulated product to stability studies under extreme conditions.

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

Even if one is directed to the use of polyols (mannitol, xylitol, maltitol, etc.) as an excipient, since these excipients possess compaction and solubility properties equivalent to those of lactose, one skilled in the art is likely to reject the direction . One skilled in the art is aware of two main negative factors known in the art.

Firstly, these classes of excipients have a detrimental effect on transit time in the small intestine and consequently influence drug absorption (Guideline for Bioequivalence Research - CPMP/EWP/QWP/1401/98 Rev. 1/ Corr).

Contrary to all expectations of one skilled in the art, it is possible to obtain an immediate release oral pharmaceutical composition that satisfies all requirements and that can be modified for robust production. Specifically, it is possible to create an immediate-release fixed-dose 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 (specifically, the current commercial mono-products).

These facts are disclosed to illustrate the technical problem addressed by the present disclosure.

GENERAL DESCRIPTION

The present disclosure relates to an immediate release fixed dose combination pharmaceutical composition comprising the active pharmaceutical ingredients (API) donepezil and memantine for the treatment of moderate to severe Alzheimer's disease.

The invention is defined by the claims. Any matter outside the scope of the claims is provided for informational purposes only.

Another aspect of the present disclosure is the use of the composition of the present disclosure in the treatment or therapy of moderate to severe Alzheimer's disease.

Another aspect of the present disclosure is an immediate release oral fixed dose combination 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;

wherein memantine or a pharmaceutically acceptable salt and donepezil or a pharmaceutically acceptable salt are the only active ingredients;

from 45.0% by weight to 60.0% by weight of 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; wherein the dissolution rate of memantine and donepezil in a pH 1 dissolution test solution is greater than 90% within 5 minutes.

The immediate release oral fixed dose combination pharmaceutical composition of the present invention has a dissolution rate of memantine and donezepil in a pH 1 test solution that is greater than 90% in 5 minutes.

The composition of the present disclosure surprisingly allows for an improved dissolution rate, a suitable disintegration rate and better shelf storage stability.

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

The disintegration test is provided to determine whether tablets, capsules or granules disintegrate within the prescribed time period when placed in a liquid medium under the experimental conditions. The experimental procedure and requirements for disintegration differ depending on the groups of dosage forms: uncoated or plain-coated tablets; delayed-release tablets and capsules (i.e., tablets or capsules that are formulated with an acid-resistant or enteric coating); buccal tablets, sublingual tablets, tablets for oral suspension, tablets for oral dissolution, orally disintegrating tablets (odts) and chewable tablets; effervescent tablets or granules. For tablets that disintegrate orally, the term 'in vitro disintegration time' means that a tablet disintegrates in the oral cavity primarily 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 liquid medium. The disintegration test of plain or uncoated tablets is performed using water at 37°C, for a maximum time of 15 minutes.

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

In one embodiment for best results, the point estimates 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 best results, the composition is bioequivalent and the bioequivalence of the composition is provided by a 90% CI (confidence interval) for the geometric mean ratio of AUC for donepezil and memantine in plasma from 80.00 to 125.00% and using a 90% CI for the geometric mean ratio of Cmax for donepezil and memantine in plasma from 80.00 to 125.00%, with the point estimates from 95.00 to 125.00%. 105.00%.

In one embodiment for best results, the composition is bioequivalent and the bioequivalence of the composition is provided by a 90% CI for the geometric mean ratio of AUC for donepezil and memantine in plasma from 90.00 to 111.00% and using a 90% CI for the geometric mean ratio of Cmax for donepezil and memantine in plasma from 90.00 to 111.00%, with the point estimates from 95.00 to 105.00%.

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

In one embodiment for best results, the composition of the present disclosure may comprise from 45.0% by weight to 60% by weight of mannitol; preferably from 45.0% by weight to 55.0% by weight of mannitol.

In one embodiment for best results, the composition of the present disclosure can disintegrate in greater than or equal to 2 min, using water at 37°C as the liquid medium.

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

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

In one embodiment for best results, the composition of the present disclosure may comprise 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 an embodiment for better results, the dissolution rate of memantine and donepezil in a pH 1 dissolution test solution is greater than 92% within 5 minutes, preferably greater than 93% within 5 minutes, which more preferably greater than 95% within 5 minutes.

In one embodiment for better results, the composition of the present disclosure may comprise less than 2.5% by weight of memantine-lactose adduct (MLA) relative to the weight of memantine, preferably less than 1.4% by weight, more preferably less than 1.0% by weight.

In an embodiment for better results, the composition of the present disclosure may further comprise:

one or more disintegrants;

one or more binders;

one or more diluents;

one or more lubricants;

optionally one or more sliders;

other pharmaceutically acceptable excipient(s).

In one embodiment for best results, the composition of the present disclosure may comprise

from 2% by weight to 30% by weight of one or more disintegrants;

from 0.5% by weight to 10% by weight of one or more binders;

from 5% by weight to 80% by weight of one or more diluents;

from 0.1% by weight to 5% by weight of one or more lubricants.

In one embodiment for best results, the composition of the present disclosure may comprise

one or more disintegrants that are selected from a 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 mixtures of the same; one or more binders that are selected from a list consisting of: hydroxypropyl cellulose (HPC), low substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polyethylene glycol, maltodextrin, pregelatinized starch, polymethacrylates, alginate sodium, polyvinylpyrrolidone (povidone), vinylpyrrolidone/vinyl acetate copolymer (copovidone) and mixtures thereof;

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

In an embodiment for better results, the composition of the present disclosure may comprise:

from 5% by weight to 25% by weight of corn starch;

from 5% by weight to 20% by weight of croscarmellose sodium;

from 1% by weight to 4% by weight of hydroxypropylcellulose (HPC);

from 45.0% by weight to 60% by weight of mannitol;

from 5% by weight to 20% by weight of microcrystalline cellulose;

from 0.1% by weight to 5% by weight of magnesium stearate;

wherein all weight % are relative to the total weight of the composition.

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

Another aspect of the present disclosure relates to a procedure for the manufacture of an immediate release oral fixed dose combination pharmaceutical composition of the present disclosure, comprising the steps of:

prepare a homogeneous combination that comprises

donepezil or a pharmaceutically acceptable salt, in particular donepezil hydrochloride, memantine or a pharmaceutically acceptable salt, in particular memantine hydrochloride, from 45.0% by weight to 60% by weight of mannitol;

one or more disintegrants, one or more binders and one or more diluents;

obtain granules by means of wet granulation;

dry the wet granules and sift;

combine the granules with one or more lubricants;

compress the final combination to give a tablet;

optionally film coat the tablet.

BRIEF DESCRIPTION OF THE DRAWINGS

The following figures provide preferred embodiments to illustrate the disclosure and should not be construed as limiting the scope of the invention.

Figure 1 shows an XRPD of donepezil hydrochloride form I.

Figure 2 shows an XRPD of memantine hydrochloride form I.

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

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

DETAILED DESCRIPTION

The present disclosure relates to an immediate release fixed dose combination pharmaceutical composition comprising 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 their hydrochloride salt forms, that is, as memantine hydrochloride (memantine HCl) and donepezil hydrochloride (donepezil HCl).

In an even 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 manufactured according to procedures known in the art, for example, as disclosed in EP 0392 059. Memantine HCl in crystalline form I can be manufactured according to WO 2006/076560.

Donepezil can be manufactured according to procedures known in the art, for example, as disclosed in EP 0296560. Donepezil HCl in crystalline form I can be manufactured according to US 6,140,321.

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

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

In one embodiment, the immediate release oral fixed dose combination pharmaceutical composition according to the present disclosure does not contain lactose.

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

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

In another aspect of the present disclosure, the immediate-release oral fixed-dose combination pharmaceutical composition has a release profile for memantine that results in a 90% CI for the ratio of the geometric means of AUC (area under the curve plasma concentration versus time) for the test product (present disclosure) and Ebixa® (reference product) from 80.00 to 125.00%, more preferably from 90.00 to 111.00 %.

In a further aspect of the present disclosure, the immediate-release oral fixed-dose combination pharmaceutical composition has a release profile for memantine that results in a 90% confidence interval (90% CI) for the ratio of the geometric means of Cmax (maximum plasma concentration) for the test product (present disclosure) and Ebixa® (reference product) of from 80.00 to 125.00%, more 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 disclosure may additionally comprise 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, it should be understood that the terms active ingredient(s), disintegrant(s), binder(s), diluent(s), lubricant(s), glidant(s), etc. They include a single compound, but also multiple compounds.

In one embodiment, the pharmaceutically acceptable disintegrant(s) include, but are not limited to, starch, carboxymethyl cellulose (carmellose), cross-linked carboxymethyl cellulose (croscarmellose), sodium starch glycolate, hydroxypropyl cellulose, low substitution (L-HPC), carboxymethyl starch, polyvinylpyrrolidone, crospovidone and mixtures thereof. Preferably, the pharmaceutical composition comprises from 2% by weight to 30% by weight of the disintegrants corn starch and/or croscarmellose sodium. In particularly preferred embodiments, the pharmaceutical composition comprises from 5% by weight to 25% by weight of corn starch and from 5% by weight to 20% by weight of 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 methyl cellulose (HPMC), methylcellulose, hydroxyethylcellulose, ethylcellulose, polyethylene glycol, maltodextrin, pregelatinized starch, polymethacrylates, sodium alginate, polyvinylpyrrolidone (povidone), vinylpyrrolidone/vinyl acetate copolymer (copovidone) and mixtures thereof. The preferred binder is hydroxypropyl cellulose (HPC).

In a preferred embodiment, the amount of one or more binders is from 0.5% by weight to 10% by weight, more preferably from 1% by weight to 5% by weight. In a particularly preferred embodiment, the pharmaceutical composition of the present disclosure comprises from 1% by weight to 4% by weight of 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 disclosure comprises from 5.0% by weight to 80.0% by weight of one or more diluents.

In one embodiment, the pharmaceutical composition of the present disclosure comprises from 5% by weight to 20% by weight of microcrystalline cellulose relative to the total weight of the composition. In one embodiment, the pharmaceutical composition of the present disclosure comprises from 45.0% by weight to 60% by weight of mannitol, preferably from 45.0% by weight to 55% by weight of mannitol relative 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 present disclosure, the sum of the amount of the pharmaceutically active ingredients and the amounts of diluents (microcrystalline cellulose and mannitol) is from 190 mg to 210 mg. Furthermore, the sum of the amount of memantine or a pharmaceutically acceptable salt thereof and the amount of diluents (microcrystalline cellulose and mannitol) is from 180 mg to 200 mg.

In one embodiment, suitable lubricant(s) include, but are not limited to, magnesium stearate, calcium stearate, sodium stearate, stearic acid, sodium glyceryl behenate, stearyl sodium fumarate and mixtures thereof. Preferably, the pharmaceutical composition of the present disclosure comprises from 0.1% by weight to 5% by weight of one or more lubricants. In a particularly preferred embodiment, the pharmaceutical composition of the present disclosure comprises from 0.1% by weight to 5% by weight of magnesium stearate relative to the total weight of the composition.

In one embodiment, the pharmaceutical composition of the present disclosure optionally comprises pharmaceutically acceptable glidant(s) such as colloidal silicon dioxide, talc, magnesium carbonate and mixtures thereof. The amount of slider(s) is preferably from 0.1% by weight to 1.5% by weight relative to the total weight of the composition.

Another aspect of the present disclosure relates to procedures for the manufacture of the immediate release oral fixed dose pharmaceutical composition.

In one embodiment, the method of preparing the pharmaceutical composition of the present disclosure comprises a) mixing pharmaceutically effective amounts of donepezil and memantine, or a pharmaceutically acceptable salt thereof, 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 to give a plurality of tablets; d) optionally coating the tablets.

In another embodiment, the method of preparing the pharmaceutical composition of the present disclosure comprises a) mixing pharmaceutically effective amounts of donepezil and memantine, or a pharmaceutically acceptable salt thereof, with at least one diluent, optionally one or more binders and optionally one or more disintegrants; b) granulating the premix, in a manner known to a person skilled in the art, to obtain a plurality of granules; c) mixing the granules with a lubricant and optionally with one or more pharmaceutically acceptable excipients; d) compressing the final mixture to give a plurality of tablets; e) optionally coating the tablets.

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 obtained granules are dried before the subsequent steps. Optionally, wet granules may require an intermediate stage of wet milling, prior to drying, through a relatively coarse mesh to break up larger agglomerates and promote a faster drying process. For example, the granules can be dried in a fluidized bed dryer or a static bed oven. Preferably, the granules are dried in a fluidized bed dryer. Optionally, the dried granules are ground in a suitable mill. Preferable mills are impact mills, cutting mills or sieving mills. Most preferably, a sieving mill is used. The tablets are preferably coated in a manner known to those skilled in the art. Preferably, the coating contains color pigments.

EXAMPLES

EXAMPLE 1 - Qualitative and quantitative composition of the lactose-free fixed dose combination compositions according to the present disclosure

Table 2 - Donepezil HCl Memantine HCl Tablets according to the present disclosure

The pharmaceutical compositions of Example 1 were prepared by a conventional wet granulation technique comprising the following steps: a) mixing donepezil HCl and memantine HCl, mannitol, microcrystalline cellulose, corn starch, hydroxypropylcellulose and croscarmellose; b) granulate the mixture with water to obtain a wet mass; c) optionally grind the wet mass; c) dry the wet dough; e) grind the dried granules; f) combine the dried granules with lubricant; f) compressing the lubricated mixture to give a plurality of tablets; g) optionally coating the tablets by procedures well known in the art.

REFERENCE EXAMPLE (R1)

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

The tablets obtained 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 pharmaceutically active ingredients and the amounts of diluents (microcrystalline cellulose and lactose monohydrate) is from 190 mg to 210 mg. Furthermore, the sum of the amount of memantine or a pharmaceutically acceptable salt thereof and the amount of diluents (microcrystalline cellulose and lactose monohydrate) is from 180 mg to 200 mg.

Table 3 - Donepezil HCl Memantine HCl Tablets of the 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 composition at fixed doses, the higher the amount of the memantine-lactose adduct (MLA) impurity.

When lactose was replaced by mannitol, surprisingly no memantinalactose adduct (MLA) impurity was detected (Table 6). Therefore, the composition of the present disclosure is more stable.

Table 6 - Memantine-lactose adduct (MLA) content

Diluent ratio: memantine60°C/100% RH (4 days)

(N.D.=not detected)

(*) composition prepared according to example 1.

Dissolution tests

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

Table 7 - Tablet in vitro dissolution parameters

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

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

Table 10 - Dissolution data of memantine and donepezil (%) of tablets of the reference example (lactose ratio: memantine HCl = 7.38)

Table 11 - Data related to the bioequivalence of the composition of the present disclosure with respect to EBIXA® and with respect to ARICEPT®

1) Reference: ARICEPT® 2) Reference: EBIXA®

It is well known in the scientific community that mannitol can cause difficult adsorption of APIs and, in fact, the Guideline for Bioequivalence Research (CPMP/EWP/QWP/1401/98 Rev. 1/Corr) describes that mannitol can affect gastrointestinal transit and, therefore, the bioavailability of a drug.

Table 12 - Data related to dissolution and stability of the composition

Surprisingly, in the presence of mannitol, donepezil and memantine were found to be bioequivalent to the mono-products, allowing the conclusion that mannitol does not affect the bioavailability of both substances when formulated as a combination composition at fixed doses of immediate release. The composition according to the present disclosure does not produce different absorption levels compared to products containing only memantine or only donepezil.

The results show that, surprisingly, the composition of the present disclosure allows an improved dissolution rate, an improved disintegration rate and an improved shelf storage stability.

Accordingly, preferred embodiments of the present disclosure relate to immediate-release oral pharmaceutical compositions that are bioequivalent compared to only memantine (specifically, with the reference product EBIXA®) and compared to only donepezil (specifically, with the reference product reference ARICEPT®).

The term “comprising” when used herein is intended to indicate the presence of the indicated elements, integers, steps, components, but does not rule out the presence or addition of one or more other elements, integers, steps, components or groups thereof.

When intervals are provided, the extreme points are included. Furthermore, it should be understood that, unless otherwise indicated or otherwise apparent from the context and/or the understanding of one of ordinary skill in the art, values expressed as ranges may assume any specific value within the intervals indicated in different embodiments of the invention, up to the tenth of the unit of the lower limit of the interval, unless the context clearly indicates otherwise. It should also be understood that, unless otherwise indicated or otherwise apparent from the context and/or the understanding of one of ordinary skill in the art, values expressed as ranges may assume any subrange within the given range, in which the extreme points of the subinterval are expressed to the same degree of precision of the tenth of the unit of the lower limit of the interval.

The disclosure should in no way be construed as being restricted to the described embodiments, and one of ordinary skill in the art will foresee many possibilities for modifications thereof.

The previously described embodiments are combinable.

The following claims further set forth particular embodiments of the disclosure.

Claims (11)

1. Immediate-release oral fixed-dose combination pharmaceutical composition for 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; wherein memantine or a pharmaceutically acceptable salt and donepezil or a pharmaceutically acceptable salt are the only active ingredients; from 45.0% by weight to 60.0% by weight of mannitol; wherein the pharmaceutical composition is lactose free; and less than 1.0% by weight of reducing sugars in relation to the total weight of the composition. 2. The composition for use according to the preceding claim, comprising from 45.0% by weight to 55.0% by weight of mannitol. 3. The composition for use according to the preceding claims, comprising less than 0.6% by weight of reducing sugars in relation to the total weight of the composition, preferably less than 0.4% by weight. 4. The composition for use according to the preceding claims, comprising 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 for memantine is memantine hydrochloride, preferably in amounts of from 5 mg to 20 mg per dose. 6. The composition for use according to any of the preceding claims, wherein the pharmaceutically acceptable salt for donepezil is donepezil hydrochloride, preferably in amounts of from 5 mg to 10 mg per dose. 7. The composition for use according to any of the preceding claims, comprising less than 2.5% by weight of memantine-lactose adduct (MLA) relative to the weight of memantine, preferably less than 1.4% by weight , more preferably less than 1.0% by weight. 8. The 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 sliders; other pharmaceutically acceptable excipient(s). 9. The composition for use according to any of the preceding claims wherein the composition comprises: one or more disintegrants that are selected from a 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 mixtures of the same; one or more binders that are selected from a list consisting of: hydroxypropyl cellulose (HPC), low substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polyethylene glycol, maltodextrin, pregelatinized starch, polymethacrylates, alginate sodium, polyvinylpyrrolidone (povidone), vinylpyrrolidone/vinyl acetate copolymer (copovidone) and mixtures thereof; one or more diluents that are selected from a 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 that are selected from a 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. Procedure for the manufacture of a pharmaceutical composition according to any of claims 1 to 10, comprising the steps of: prepare a homogeneous combination that comprises donepezil or a pharmaceutically acceptable salt, in particular donepezil hydrochloride, memantine or a pharmaceutically acceptable salt, in particular memantine hydrochloride, from 45.0% by weight to 60.0% by weight mannitol one or more disintegrants, one or more binders and one or more diluents; obtaining granules by means of wet granulation; dry the wet granules and sift; combine the granules with one or more lubricants; compress the final combination to give a tablet; optionally film coat the tablet.