HK1076605B - Formulations - Google Patents

Description

Formulation of

Technical Field

The present invention relates to pharmaceutical compositions for oral administration of active compounds.

The active compounds contemplated for use in the present invention are 2- [4- (diphenylmethyl) -1-piperazinyl ] -acetic acid of the general formula I and amides thereof.

General formula I

Wherein the content of the first and second substances,

R₁is a-COOH group or-CONH₂A base, and

X₁and X₂Each represents a hydrogen atom, a halogen atom, a straight chain or branched chain C₁-C₄Alkoxy or trifluoromethyl and their pharmaceutical useAcceptable salts, geometric isomers, enantiomers, diastereomers, and mixtures thereof.

Background

The compounds according to formula I are orally active and selective histamine H₁-a receptor antagonist. They are described in EP0058146, the contents of which are incorporated herein by reference. Examples of such compounds include cetirizine, under the trade name cetirizineIts dihydrochloride form, the (S) isomer, levocetirizine, is commercially available under the trade nameIts dihydrochloride form and its dihydrochloride form efletirizine are commercially available.

A series of problems encountered with oral formulations of these active compounds is their taste caused by the bitter taste of the active compounds of the general formula I. This is particularly evident in chewable tablets and in fast dissolving formulations.

Several methods have been used in the prior art to mask the bitter taste of most active substances.

For example, US5,244881 teaches that the bitter taste of the active substance imipramine or its derivative trimipramine can be masked by embedding it in cyclodextrin. Such embedded complexes are prepared by dissolving imipramine or trimipramine and cyclodextrin in a small amount of water or solvent, carefully mixing the resulting mixture, and evaporating the mixture.

However, taste masking is not always sufficient to obtain a palatable pharmaceutical composition. Good mouthfeel often requires further addition of polyols to the composition. The term "polyol" as used herein includes xylitol, mannitol, sorbitol, glucose, sucrose, lactose, maltodextrin, alpha cyclodextrin, beta cyclodextrin, gamma cyclodextrin and polysaccharides, but is not limited thereto. Mannitol has proven to be a particularly suitable substance for improving the mouthfeel of preparations containing active compounds of the general formula I. However, such compositions have serious drawbacks. The compounds of formula I in the presence of certain polyols, including mannitol, give rise to undesirable reaction products, as disclosed for example in EP0811374a 1. This side reaction increases in the presence of water and/or at elevated temperatures. The presence of mannitol and other polyols may give rise to stability problems of the compounds of formula I.

Until now, there has been no other choice but to avoid the use of these polyols in the composition, or to coat the compounds of formula I before formulation, for example with cellulose or acrylic polymers, in order to avoid undesired reaction products.

In the first case, the use of other excipients, such as microcrystalline cellulose, impairs the taste of the tablet, and in fact, microcrystalline cellulose is not completely soluble in water and therefore may have a sandy-like feel in the mouth.

In the second case, the thickness of the coating required to avoid the reaction between the active compound of formula I and the polyol prevents a rapid release of the drug from the dosage form.

EP0811374a1 teaches that all dosage forms must be free of active alcohols, including polyols. Therefore, according to this suggestion, polyols that improve mouthfeel may not be used in all oral compositions. Example 2 of EP0811374, which states a preferred embodiment, clearly shows no taste improving polyol, the only polyol present in the composition being polyethylene glycol, a high molecular weight polyol (MW3350), which has a function different from that of the taste masking agent.

Disclosure of Invention

The object of the present invention is to overcome the disadvantage of losing stability in the presence of polyols, to a certain extent making it palatable and avoiding undesirable changes in the product properties.

The problem solved by the present invention is to improve the taste and mouthfeel of oral compositions containing an active compound of formula I and a mouthfeel improving polyol, while avoiding any stability reduction problems and maintaining optimal release kinetics of the active compound.

Taste-masking polyols are generally solid and have a molecular weight of less than 3000.

The inventors have found that the loss of stability caused by the interaction of the active compound of formula I with the polyol is associated with a decrease in the molecular weight of the polyol.

TABLE 1 molecular weight of certain polyols

Polyhydric alcohols	MW
		Xylitol, its preparation method and use	152.15
Mannitol	182.17
		Sorbitol	182.17
Glucose	198.17
		Sucrose	342.30
Lactose	342.30
		Maltodextrin	Starting from 900.00
alpha-Cyclodextrin	972.00
		Beta-cyclodextrin	1135.00
Gamma cyclodextrin	1297.00
		Microcrystalline cellulose	36000

Generally, low molecular weight polyols, such as xylitol, mannitol, sorbitol, glucose or sucrose (see table 1) are active or very active and result in a large amount of undesired reaction products. On the other hand, high molecular weight polyols, such as cyclodextrins (see Table 1), are less active.

Surprisingly, the relationship between molecular weight and activity is not applicable to lactose. Lactose has the same molecular weight as sucrose, but shows little activity as the active compound of formula I.

Very reactive polyols may thus be defined as those polyols having a molecular weight below 300. The reactive polyol has a molecular weight between 300 and 950, with the exception of lactose.

The inventors have further found that even reactive and very reactive polyols and reactive compounds of the formula I do not lead to intolerable amounts of undesirable reaction products if the molar ratio of these polyols to reactive compound does not exceed 10. If the molar ratio of the reactive or very reactive polyol to the reactive compound of the formula I is not higher than 5, the percentage of undesired side reaction products is reduced even further.

Based on these findings, the technical problem has been solved according to the present invention by providing a composition prepared from two formulations, wherein in a first formulation the active compound of formula I is contained with at most only a critical level of an active or very active polyol, and wherein in a second formulation the polyol is contained which is required to achieve a pleasant taste, but without a pharmaceutical compound. Thereby, the formation of undesired reaction products is largely eliminated and the unpleasant taste is effectively reduced or masked.

The solution to the problem is very different from the teaching of EP0811374a 1. This document teaches that the dosage form should be substantially free of active alcohol at and after the time the immediate release cetirizine component is introduced into the dosage form, and therefore, active polyols have to be excluded from the overall composition. The alcohols disclosed in EP0811374a1 perform a function completely different from the present invention, namely either as solvents (low molecular weight alcohols such as methanol, ethanol, isopropanol and glycerol) or as high molecular weight compounds (polyethylene glycol) to facilitate the release of pseudoephedrine. Prior to the addition of cetirizine, low molecular weight alcohols are removed to prevent undesirable reaction products.

According to the present invention, the reactive polyol may be present in any number in the second layer. Indeed, the presence of solid polyols having a molecular weight of less than 3000 in the second formulation according to the invention is a need for an improved mouthfeel, which is necessary for chewable or fast-dissolving pharmaceutical compositions.

EP0811374a1 is not concerned with taste masking as a dosage form, since it is not intended to be dispersed in the mouth, but rather to be swallowed in its entirety.

Thus, the present invention relates to an oral pharmaceutical composition comprising at least two separate compounds

The formula is as follows:

-a first formulation comprising an active ingredient selected from 2- [4- (diphenylmethyl) -1-piperazinyl ] -acetic acid and amides of general formula I.

General formula I

Wherein the content of the first and second substances,

R₁is a-COOH group or-CONH₂The base group is a group of a compound,

X₁and X₂Each represents a hydrogen atom, a halogen atom, a straight chain or branched chain C₁-C₄And pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers and mixtures thereof, wherein the molar ratio between the polyol and the active compound of formula I is greater than 10, the first formulation does not contain a polyol having a molecular weight of less than 300; and

-a second formulation comprising one or more solid polyols having a molecular weight of less than 3000 and no drug.

A solid polyol is defined as a polyol that is not liquid at room temperature and atmospheric pressure.

In a preferred embodiment, the first formulation does not contain polyols having a molecular weight of less than 950, with the exception of lactose, at a molar ratio between polyol and active compound of formula I of more than 10. Since lactose has no significant reactivity with the active compound of formula I, it can be present in high proportions.

In another preferred embodiment of the invention, the first formulation does not contain polyols having a molecular weight of less than 300 at a molar ratio between polyol and active compound of formula I of more than 5.

In a more preferred embodiment, the first formulation does not contain polyols having a molecular weight of less than 950, except lactose, when the molar ratio between polyol and active compound of formula I exceeds 5.

In an even more preferred embodiment, the first formulation does not contain polyols having a molecular weight of less than 300.

In another more preferred embodiment, the first formulation does not contain polyols having a molecular weight of less than 950, with the exception of lactose.

As used in the present invention, the term active compound of formula I relates to 2- [4- (diphenylmethyl) -1-piperazinyl ] -acetic acid and the amides of formula I as defined above and to non-toxic pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers and mixtures thereof (racemates). In a preferred embodiment, the active compound in the first formulation is cetirizine dihydrochloride, levocetirizine dihydrochloride or efletirizine dihydrochloride.

The term drug includes active compounds of formula I as well as other drugs.

Preferably, the oral pharmaceutical composition contains only one active ingredient.

The polyols used in the second formulation are typically those having properties that reduce the bitterness of the active compound of formula I and improve the mouthfeel of the formulation. Examples include sorbitol, xylitol, maltitol, glucose, sucrose, polysaccharides and preferably mannose.

The formulation can be prepared into powder, granule, solution or suspension.

The solution or suspension is used for coating.

The first and/or second formulation may also contain an alkaline (alkalizing) substance, preferably sodium citrate. Such materials further reduce the production of undesirable reaction products between the polyol and the reactive compound of formula I.

The first formulation may contain one or more additional excipients such as colloidal anhydrous silicon dioxide, microcrystalline cellulose, magnesium stearate, flavoring, coloring agents, or mixtures thereof.

The first formulation may also contain polyols, provided that they do not fall within the specific molecular weights set forth above at the specific molar ratios. The first formulation may further comprise non-polyol sweeteners such as acesulfame K, aspartame, saccharin, sodium saccharin, cyclamate.

Flavoring agents suitable for use in the present invention include essential oils and synthetic flavoring agents such as citrus fruit tree oil, fruit tree essence, peppermint oil, spearmint oil, clove oil, wintergreen tree oil, anise, eucalyptus, and the like. Other artificial flavoring agents known in the art are also within the scope of the present invention.

By the present invention, its design includes all forms of oral compositions, including tablets, chewing gums, effervescent tablets and dry syrups.

Dry syrup is defined as a solid preparation such as a powder or granules, intended for oral administration in this form or after addition to a liquid.

Accordingly, the present invention relates in a particular embodiment to a bilayer tablet wherein each layer is prepared from one of the formulations.

The powders of both formulations were mixed separately and then compressed in a double layer rotary tablet press.

The term compaction is defined as the reduction of the volume of the powder bed due to the application of pressure (see "Pharmaceutical powder compaction technology") consisting ofAlderborn and ChryserEditors, p.vii, MarcelDekker, inc., new york).

In another embodiment, the invention relates to a three layer tablet wherein an inert layer separates the layers prepared from the two formulations.

Also further tablet designs according to the invention include designs such as "sandwich" where an inner layer prepared from one formulation is coated on both sides with layers prepared from the other formulation, or bi-layer tablets having an inner core prepared from one formulation and an outer shell prepared from the other formulation, or multi-layer tablets containing further layers in addition to the first and second layers prepared from the first and second formulations.

A further embodiment of the invention relates to a dry syrup which is prepared from a mixture of two formulations prepared in the form of granules, one containing the active compound of the formula I and one containing a polyol.

In this case, the powder formulations are mixed separately and then compressed, milled and sieved separately to obtain two kinds of granules. These particles are mixed together to give the final product.

Compression of each formulation separately is preferred to produce an effective dry syrup.

The term compaction is defined as the transformation of a powder into a shaped product by powder compaction (see "Pharmaceutical powder compaction technology") consisting ofAlderborn and ChryserEditors, p.vii, Marcel Dekker, inc., new york).

Yet a further embodiment of the invention relates to a chewing gum, for example consisting of an inner core prepared from a first formulation and additionally comprising a gum base, and a coating prepared from a second formulation. Alternatively, the chewing gum may consist of an inner core prepared from the second formulation and additionally comprising a gum base, and a coating prepared from the first formulation.

The gum base used in the preparation of the chewing gum used in the present invention may be any suitable gum base known in the art, including natural and synthetic gum bases.

All compositions according to the invention may contain one or more additional outer coatings.

When cyclodextrin is present, the molar ratio of cyclodextrin to the active of formula I ranges from 10: 1 to 1: 1.

The weight ratio of the first formulation to the second formulation is from 1: 20 to 20: 1.

The composition according to the invention is dispersible in the mouth without the need for water intake, in contrast to the dosage forms disclosed in EP0811374a1 which have to be swallowed with water. The compositions of the invention are, for example, in the form of orodispersible tablets (tablets are placed in the mouth, they disperse rapidly before swallowing), which may be chewed or intended to be bitten or sucked.

The results of the tests demonstrate that the composition dispersed in the mouth according to the invention is bioequivalent to a swallowable dosage form.

Preferably, the composition according to the invention is an immediate release formulation, i.e. the pharmaceutical formulation does not or hardly affect the active ingredient to the site of actionTransportmentSpeed.

Another embodiment relates to a method of preparing a composition according to the present invention comprising separately preparing the first formulation, the second formulation and combining the two formulations. These formulations are obtained by conventional techniques such as compression, direct compression, granulation, wet granulation, coating. This technique is known to the person skilled in the art.

Other taste masking techniques may be used together in the present invention. Taste masking properties can be obtained by applying taste masking techniques to one or both of the formulations.

The invention is illustrated by the following examples.

Example 1 cetirizine double layer chewable tablets.

The two formulations were prepared separately. The compositions of these formulations are given in tables 2 and 3.

TABLE 2 combination of dual-layer tablet formulation of cetirizine dihydrochloride

TABLE 3 mannitol formulation composition of bilayer tablet

The cetirizine and mannitol formulation is then compressed in a rotary bi-layer tablet press (e.g., Courtoy 292/43).

Tablets were placed in aluminum/aluminum blister (Alu/Alu blister) and High Density Polyethylene (HDPE) bottles for 3 months at 25-60% Relative Humidity (RH), 30-60% RH, and 40-75% RH. Table 4 gives the results of the stability studies.

Table 4. stability study of cetirizine chewable bilayer tablets.

BLQ: below the limit of quantitation (═ 0.1%)

The water content, the breakage resistance, the disintegration time, the dissolution kinetics were all determined and all tablets met the specifications whatever the storage conditions.

Example 2 cetirizine dry syrup.

Both formulations were prepared separately. The compositions of these formulations are given in tables 5 and 6.

Table 5. composition of cetirizine dihydrochloride formulation of dry syrup.

TABLE 6 composition of mannitol formulation of dry syrup.

Formulations A, B, C and D were separately pressed, milled and sieved to give granules A ', B', C 'and D'. The final composition of the dry syrup was obtained by mixing the granules a ', B', C 'and D' according to the proportions described in table 7.

TABLE 7 Dry syrup compositions

The dry syrup was placed in aluminum/aluminum blisters for 10 weeks at 25-60% RB, 30-60% RH, and 40-75% RH. Table 8 gives the percentage of undesired reaction products determined in the formulation.

Table 8.10 percentage of undesired reaction products in dry syrup after weeks.

All formulations met the specification.

Example 3 cetirizine chewing gum.

A composition of a chewing gum consisting of an inner core containing cetirizine obtained by compression and a coating containing a polyol is given in table 9.

TABLE 9 composition of chewing gum.

Like the bilayer tablets and the dry syrup, the chewing gum meets the stability requirements.

Claims (17)

1. A pharmaceutical composition in the form of a multi-layer tablet comprising two separate formulations:

-a first formulation comprising an active compound selected from 2- [4- (diphenylmethyl) -1-piperazinyl ] -acetic acid having general formula I and amides thereof.

General formula I

Wherein the content of the first and second substances,

R₁is a-COOH group or-CONH₂A base, and

X₁and X₂Each represents a hydrogen atom, a halogen atom, a straight chain or branched chain C₁-C₄Alkoxy or trifluoromethyl and their pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers and mixtures thereof, which comprises a cyclodextrin in the first formulation and which is free of polyols having a molecular weight of less than 300 when the molar ratio between the polyol and the active compound of formula I is higher than 10; the first formulation further comprises one or more excipients selected from colloidal anhydrous silicon dioxide, microcrystalline cellulose, magnesium stearate, flavoring agents or coloring agents; and

-a second formulation comprising one or more solid polyols having a molecular weight of less than 3000 and being free of any drug;

wherein each layer of the multi-layer tablet is prepared from one of the formulations.

2. A composition according to claim 1, wherein the first formulation does not contain polyols having a molecular weight of less than 950, with the exception of lactose, at a molar ratio between polyol and active compound of formula I of greater than 10.

3. The composition according to claim 1, wherein the first formulation is free of polyols having a molecular weight of less than 300 at a molar ratio between polyol and active compound of formula I of greater than 5.

4. A composition according to any of claims 1 to 3 wherein the first formulation is free of polyols having a molecular weight of less than 300.

5. A composition according to any one of claims 1 to 3, wherein the first formulation does not contain polyols having a molecular weight of less than 950, with the exception of lactose, at a molar ratio between polyol and active compound of formula I of greater than 5.

6. A composition according to any of claims 1 to 3 wherein the first formulation does not contain a polyol having a molecular weight of less than 950, with the exception of lactose.

7. A composition according to any one of claims 1 to 3, wherein the polyol in the second formulation is mannitol.

8. A composition according to any one of claims 1 to 3 wherein at least one of the formulations further comprises an alkaline material.

9. The composition of claim 8 wherein the alkaline material is sodium citrate.

10. A composition according to any of claims 1 to 3 wherein the first formulation further comprises a non-polyol sweetener.

11. The composition according to claim 10, wherein the non-polyol sweetener is selected from acesulfame K, aspartame, saccharin, sodium saccharin or cyclamate.

12. A composition according to any one of claims 1 to 3 wherein the active compound in the first formulation is cetirizine dihydrochloride, levocetirizine dihydrochloride or efletirizine dihydrochloride.

13. A composition according to any one of claims 1 to 3, wherein it is in the form of a chewing gum, a tablet or an effervescent tablet.

14. A composition according to claim 13, in which the inert layer separates the layers prepared from the two formulations.

15. A composition according to claim 13, wherein there is an inner core prepared from one formulation and an outer shell prepared from another formulation.

16. A composition according to claim 13, wherein it is a chewing gum comprising

An inner core prepared from the first formulation and additionally containing a gum base, and

-a coating prepared from the second formulation.

17. A composition according to claim 13, wherein it is a chewing gum comprising

An inner core prepared from the second formulation and additionally containing a gum base, and

-a coating prepared from the first formulation.