TW201440808A - Pharmaceutical composition for oral administration comprising fexofenadine and process for preparing thereof - Google Patents

Abstract

The present invention relates to pharmaceutical compositions for oral administration, said compositions comprising high(methyl)pectin, glycerol, water and fexofenadine, or a pharmaceutically acceptable salt thereof. The invention also relates to the uses of these compositions as a medicament and to the process for preparing said compositions.

Description

Oral pharmaceutical composition containing FEXOFENADINE and preparation method thereof

This invention relates to formulations of fexofenadine or a pharmaceutically acceptable salt thereof. More particularly, the invention relates to oral pharmaceutical compositions comprising high (methyl) pectin, glycerin, water, and phenoxyphenidine or a pharmaceutically acceptable salt thereof. The invention also relates to a method of preparing a pharmaceutical composition and the use of the pharmaceutical composition as a medicament.

Fisofenadine is well known as an antihistamine compound having selective peripheral H1 receptor antagonist activity. The phenoxantazine as a substance is usually used in the form of phenoxyphenidine hydrochloride represented by the following formula (I):

A process for the preparation of phenoxyphene hydrochloride is known from US 6,113,942. In addition, thisofenadine hydrochloride is commercially available under the trade name ALLEGRA®. ALLEGRA is a coated lozenge suitable for oral administration. The lozenge containing the salt is sufficiently large due to some properties of phenoxyphene hydrochloride. In fact, the total amount of phenoxyphenidine hydrochloride in the tablet should not exceed 30% by weight based on the total weight of the tablet. Therefore, some patients (especially elderly patients and children) may have difficulty swallowing a relatively large lozenge. In addition, the administration of tablets usually requires ingestion of liquid to aid in swallowing. pharynx. In daily life, the patient does not always have liquid on hand. These problems can lead to poor compliance or disobedience to treatment.

Other formulations of phenoxyphene have been further proposed in the industry.

WO 03/041683 discloses an orally dispersible lozenge containing phenoxyphenidine. Although oral dispersible formulations can be swallowed more easily, some patients may find it unpleasant to take.

WO 00/21510 discloses fensofinadine liquid formulations suitable for nasal or ocular administration. These two types of administration can cause concern in some specific topical therapies and have limited bioavailability. However, phenoxyphene is more active when administered orally. This explains why this latter route of administration is generally better.

Therefore, there is still a need in the industry for oral new phenoxyphene formulations suitable for most patients, including the elderly and children. In particular, the formulation should be easy to swallow and preferably ingest without the use of a liquid.

Accordingly, the present invention relates to a pharmaceutical composition for oral administration comprising: -1 to 3.5 wt%, preferably 1.5 to 3 wt% of high (methyl) pectin, - 40 to 68 wt%, preferably 48 to 62 wt. % glycerol, - 16-29 wt%, preferably 20-25 wt% water, - when present, 0-1 wt%, preferably 0.1-0.5 wt% of at least one surfactant, -3-5 wt%, Preferably, 3.5-4.5 wt% of phenoxyphenidine or a pharmaceutically acceptable salt thereof, - 12-24% by weight, preferably 15-20% by weight, can be complexed with phensophenidine or a pharmaceutically acceptable salt thereof Pharmaceutical excipients, when present, 0 to 5 wt%, preferably 0.5 to 2.5 wt%, of at least one other component selected from the group consisting of: sugar substitutes, flavoring agents and/or coloring agents, weight percent Relative to the total weight of the composition, and the pH of the composition is between It is in the range of about 2.8 to about 3.2.

It should be noted that throughout the application, the scope is intended to include limit values. The pectin is represented by the following formula (II):

In normally extracted pectin, more than 50% of the acid units are esterified. This pectin is usually classified and referred to as "high methyl ester pectin" or "high (methyl) pectin". The percentage of ester groups is referred to as the degree of esterification (DE). Preferably, the high (methyl) pectin has a DE of from about 50 to about 80, more preferably from about 65 to about 75, in accordance with the present invention. An important component of high (methyl) pectin-based compositions. In fact, high (methyl) pectin allows for the composition to be grasped once formed. In addition, the use of high (methyl) pectin makes the gelation of the composition easy to control, occurs quickly (ie in less than 2 hours), and does not require heating the composition to temperatures above 90 °C, thereby avoiding other ingredients, specific Any potential degradation of phenazophenidine or its pharmaceutically acceptable salt.

In the compositions of the invention, glycerol is introduced as an adjuvant to pectin which allows the composition to gel in the presence of water and pH adjustment. Furthermore, the presence of glycerol avoids the use of sucrose in the composition, which has heat and produces dental caries. A particular advantage of the pharmaceutical compositions of the present invention is that the compositions are free of sugar.

Preferably, the water introduced into the composition is purified water according to the U.S. and European Pharmacopoeia.

The compositions of the present invention may comprise at least one surfactant which only needs to be present in some particular embodiments. For example, the presence of a surfactant may depend on the method of preparing the pharmaceutical composition. In particular, one party after the invention disclosed below In the method, the step (i) of mixing phenoxyphenidine or its pharmaceutically acceptable salt, pharmaceutical excipient, glycerin and water may comprise adding a surfactant, depending on the particular embodiment of step (i) (see below). In this case, a surfactant is used to disperse phenoxyphenidine or a pharmaceutically acceptable salt thereof and a pharmaceutical excipient.

When present, the surfactant is preferably a nonionic surfactant. Advantageously, the surfactant is selected from the group consisting of ethylene oxide propylene oxide copolymers (for example sold under the trademark POLOXAMER), polysorbates (for example sold under the trademark TWEEN). Preferably, the surfactant is polyoxyethylene (20) sorbitan monooleate (or polysorbate 80), such as sold under the trade name TWEEN 80.

The phenoxoratinidine introduced into the composition is preferably a salt of phenoxyphenidine, more preferably phenazophene hydrochloride represented by the above formula (I). Fipprofenadine hydrochloride exists in three forms depending on the degree of hydration of the salt. Preferably, phenoxyphene hydrochloride is Form I, ie anhydrous.

Fisofenadine or a pharmaceutically acceptable salt thereof is known to be difficult to dissolve. The compositions of the present invention comprise a pharmaceutical excipient which forms a complex with phensophenidine or a pharmaceutically acceptable salt thereof. In fact, in a preferred embodiment, the pharmaceutical excipient is beta-cyclodextrin.

Furthermore, the compositions of the present invention may comprise at least one other ingredient selected from the group consisting of: a sugar substitute, a flavoring agent and/or a coloring agent.

A substitute sugar product means a food additive that mimics a sugary taste. Preferably, the so-called sugar substitutes are artificial sweeteners such as sucralose, saccharin and/or potassium sulfamate.

The flavoring agent is preferably selected from the group consisting of lime, lemon, strawberry and apple.

Colorants mean dyes, lakes and/or devitrification agents. Examples of such colorants are hematite oxide, yellow iron oxide, TiO ₂ , card red E120, FD&C Blue No. 1 aluminum lake, and the like.

To gel the composition, the pH of the composition must be adjusted to be in the range of from about 2.8 to about 3.2, preferably from about 2.9 to about 3.1. The adjustment is made by adding acid to the combination Implemented. Preferably, the acid is selected from the group consisting of citric acid, tartaric acid, phosphoric acid and/or lactic acid, and more preferably citric acid.

The pharmaceutical compositions of the invention have a water activity of less than 0.61.

"Water activity" means the availability of water (i.e., free water) that can be used by a microorganism for growth within a sample. Water activity can be measured by methods known in the art.

Preferably, the water activity is less than 0.60, more preferably less than 0.59 and still more preferably less than 0.58. This low water activity is of particular interest because it eliminates the need to add a preservative such as a paraben to the composition.

It should be noted that once gelled, the pharmaceutical compositions of the present invention form a chewable solid. In addition, the solid composition can also be inhaled for patients with few or no teeth. Therefore, the pharmaceutical composition can be easily ingested by all patients, especially the elderly and children. The pharmaceutical composition may also have a pleasant appearance and a pleasant taste: - the taste of the composition can be improved by the addition of suitable sugar substitutes and flavoring agents, and - the colorant can make the chewable composition more attractive.

All of these features make it easier for patients to be compliant with treatment.

The pharmaceutical compositions of the invention are useful as medicaments, especially as antihistamines and/or bronchodilators, and are particularly useful for the treatment of allergies and/or urticaria. Further, the pharmaceutical composition of the present invention can be used in a method for treating allergy and/or urticaria, which comprises administering to a patient a pharmaceutical composition of the present invention.

The pharmaceutical composition in solid form can be divided into a plurality of units, each unit containing a dose of phenoxyphene or a pharmaceutically acceptable salt thereof. As an example, units of 0.75 g, 1.5 g, and 3 g may each comprise a dose of 30 mg, 60 mg, and 120 mg of phenoxyphenidine or a pharmaceutically acceptable salt thereof.

As mentioned above, the pharmaceutical compositions of the present invention can form a graspable unit. Specifically, when measured by a texture analyzer, the pharmaceutical composition of 1.5 g unit has a hardness of 30 g or more, preferably in the range of 40 g to 200 g, more preferably 50 g to 150 g. By Texture analyzer measurements are known in the industry. An example of this measurement is more specifically illustrated in the examples.

The invention further relates to a process for the preparation of a pharmaceutical composition of the invention comprising the steps of: i) mixing phensophenidine or a pharmaceutically acceptable salt thereof, a pharmaceutical excipient, glycerin and water, ii) after heating, Adding high (methyl) pectin, iii) adding a sweetener, flavoring and/or coloring agent (if used), (i) heating the resulting mixture of step (ii) to between about 60 ° C and about 90 ° C The temperature in the range, preferably about 70 ° C, iv) the pH is adjusted with acid, v) the composition is formed and cooled until gelation occurs.

One of the steps (i) of the method is to dissolve phenoxyphenidine or a pharmaceutically acceptable salt thereof with a pharmaceutical excipient and to disperse the resulting complex in glycerin and water. According to the invention, this dissolution and dispersion can be carried out according to different examples.

In a first embodiment, step (i) is carried out as follows: a) mixing phenoxyphenidine or a pharmaceutically acceptable salt thereof and a pharmaceutical excipient with water, b) adding glycerin and a surfactant to the step ( In the resulting mixture of a).

More particularly, step (a) comprises several sub-steps: - first mixing the pharmaceutical excipient with a portion of the water to obtain a mixture having a paste-like consistency; - adding a portion of phenoxyphenidine or a pharmaceutically acceptable salt thereof to The mixture having a paste-like consistency is then added with another portion of water; - Finally, the remaining phenoxyphene or its pharmaceutically acceptable salt is added and then the remaining water is added.

In this step (a), a surfactant is added to disperse the different components. However, the score The dispersion is significantly improved by the gradual addition of water and phenoxyphene or its pharmaceutically acceptable salt. Furthermore, in the last substep, the remaining water is added after a contact time of at least 45 min, preferably at least 1 h.

Advantageously, step (a) may comprise the following sub-steps: - first mixing the pharmaceutical excipient with 50% (half) of the water to obtain a mixture having a paste-like consistency; - about 60% to 85% of phenoxyphene Adding or a pharmaceutically acceptable salt thereof to the mixture having a paste-like consistency, and then adding another 15% to 35% of water; - Finally, adding about 15% to 40% of phenoxyphene or its medicinal preparation The acceptable salt is then added to the remaining water (15% to 35%, depending on the amount of water added in the aforementioned substep).

In this embodiment, the percentage is relative to the total content of each component.

In a second embodiment, step (i) is carried out as follows: I. mixing water with glycerol, II. adding phensophenidine or a pharmaceutically acceptable salt thereof and a pharmaceutical excipient to the mixture of step (I) in.

More particularly, in step (II), phenoxyphenidine or a pharmaceutically acceptable salt thereof and a pharmaceutical excipient are added in powder form to the mixture of step (I), which comprises phenoxyphene Or a pharmaceutically acceptable salt thereof is combined with a pharmaceutical excipient.

The powder comprising phenoxyphenidine or a pharmaceutically acceptable salt thereof in combination with a pharmaceutical excipient can be prepared as follows:

- first mixing the pharmaceutical excipient with a quantity of water (the amount is 10% to 20% of the total weight of the two components (phenazophenidine or its pharmaceutically acceptable salt and pharmaceutical excipient)), Obtaining a mixture having a paste-like consistency;

- progressively adding all phenazophenidine or its pharmaceutically acceptable salt to a mixture having a paste-like consistency,

- The resulting paste is then dried at about 60 ° C for at least 2 hours to remove water.

- Finally the dried product is ground to obtain a powder.

It should be noted that, according to the present invention, since the added water is subsequently removed by drying, the amount of water mentioned in the powder preparation method is not considered to be within the total weight of the composition.

In this latter embodiment, the addition of a surfactant can be avoided.

Advantageously, the high (methyl) pectin of step (ii) is added after heating the mixture of step (i) to a temperature in the range of from about 35 °C to 45 °C, preferably about 40 °C.

Preferably, in step (v), citric acid, tartaric acid, phosphoric acid and/or lactic acid are used and citric acid is used more preferably to adjust the pH.

In a first preferred embodiment, the forming step is carried out by pouring the pharmaceutical composition into a mold. Advantageously, the molds can be further aligned to form a subsequently heat sealable blister package.

In a second preferred embodiment, the forming step is carried out by depositing a droplet of the pharmaceutical composition onto a cooling belt. The droplets solidify and cool as they travel with the belt. The coagulation unit is then discharged at the end of the belt and collected. The cooled zone can be made of steel or another suitable material.

Example 1: Compositions and Methods of the Invention Composition

The pharmaceutical composition of the present invention is prepared using the following ingredients:

* The percentage of each component is based on the weight percent of the total weight of the composition. ** w/w: weight / weight. ***Qs: Moderate amount.

2. Preparation method

The preparation of the pharmaceutical composition is carried out as follows.

The first step of the process aims to dissolve and disperse the phenoxyphene: 67.6 g of β-cyclodextrin and 44 g of water are mixed to form a paste mixture. Then, 12 g of phenoxyphene was added to the mixture, followed by the addition of 31 g of water, and the purpose of adding water was to avoid hardening of the mixture. Finally, add the remaining phenoxyphene and then add the remaining water.

Then 215.6 g of glycerin and 0.8 g of surfactant were added to the mixture and mixed. The mixture was heated at 40 °C. When the mixture reached 40 ° C, 8 g of high (methyl) pectin was added to the mixture.

2 g of sucralose and 2 g of Lyme flavor were added to the mixture, and then the mixture was heated to a temperature of 70 °C. The pH was adjusted using a 10% w/w citric acid solution.

The resulting mixture is a pharmaceutical composition of the invention. The composition is then poured into a plastic or metal laminate mold.

An example of a blister pack is illustrated in Figure 2. In this figure, the blister pack 1 comprises two rows of parallel cavities 2 and is reinforced by a central rib 3. Each cavity is cup-shaped. The largest diameter of the cup (on the surface of the blister pack 1) is about 20 mm and its depth is about 6.5 mm.

Each cavity was filled with 1.5 g (a dose corresponding to the dose of 60 mg of phenoxyphenidine hydrochloride) as a liquid pharmaceutical composition 4. The blister pack is then heat sealed using a foil cover sheet and the pharmaceutical composition is allowed to cool until the composition gels.

Once gelled, the pharmaceutical composition of the present invention can be easily flipped out of the mold to form a molded unit and easily grasped, as shown in FIG.

3. Water activity

The pharmaceutical composition of the present invention does not require the use of any preservatives. In particular, the addition of parabens can be avoided. This feature can be confirmed by measuring the water activity of the pharmaceutical composition of the present invention.

Water activity was measured by using a Rotronic Hygrolab device. This measurement was not carried out for the entire molding unit, but was carried out for the sample portion of the unit, which had the following dimensions: 20 mm diameter (x) 2-3 mm thickness. Cut this part out of the molding unit. The sample is then introduced into the measurement element. After a short period of time, the value can be read.

The water activity as measured was 0.58. This result is below the water activity of 0.61 which represents the upper limit, above which a preservative is required.

4. Hardness

As mentioned above, the molding unit is easy to grip. To evaluate this feature, a texture analyzer was used to measure the hardness of the cells.

method:

The texture analyzer is a TA.XT.plus texture analyzer from Stable Micro Systems® equipped with a 6mm diameter cylindrical probe and a 5kg load cell.

The parameters of the texture meter are as follows: Mode: Measuring compression force

Test speed = 1mm / s

Distance = 1mm

Trigger Type = Auto - 5.0g

The measurement system is implemented for a sample composed of molding units. The molding unit is positioned such that the surface in contact with the cup of the blister pack faces upward. Once the probe touches the surface of the sample, the probe penetrates the sample until a depth of 1 mm is reached. At this depth, the load is measured and this value represents the hardness of the sample. To evaluate the reproducibility of the measurements, 10 samples were tested.

The measured hardness is included in the range of 50 g to 100 g. Units with hardness below 30g have been determined to be unobtainable. This confirms that the molding unit of the pharmaceutical composition of the present invention is graspable.

1‧‧‧blister packaging

2‧‧‧cavity

3‧‧‧ center rib

4‧‧‧Pharmaceutical composition

The invention is further illustrated by the following examples with reference to the following examples which are not to be construed as limiting in any way: - Figure 1, which is a photograph of a mold filled with the composition of the invention, and - Figure 2, for preparation A diagram of a mold of the composition unit of Example 1.

Claims (13)

A pharmaceutical composition for oral administration comprising: 1 wt% to 3.5 wt% of high (methyl) pectin, 40 wt% to 68 wt% of glycerin, 16 wt% to 29 wt% of water, and 0 to 1 wt% of at least one Surfactant, 3 wt% to 5 wt% of fexofenadine or a pharmaceutically acceptable salt thereof, 12 wt% to 24 wt% of which can be complexed with the phenoxyphenidine or a pharmaceutically acceptable salt thereof a pharmaceutical excipient, at least one of 0 to 5 wt% selected from the group consisting of: a sugar substitute, a flavoring agent, and/or a coloring agent, the weight percentages being relative to the total weight of the composition, and The pH of the composition is in the range of 2.8 to 3.2. The pharmaceutical composition of claim 1 which has a water activity of less than 0.61. The pharmaceutical composition of claim 1 or 2 wherein the pH of the composition is adjusted by the addition of an acid to the composition. The pharmaceutical composition according to any one of claims 1 to 3, wherein the phenoxyphenazine is phenoxyphenidine hydrochloride. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical excipient is β-cyclodextrin. The pharmaceutical composition according to any one of claims 1 to 5, which is chewable. The pharmaceutical composition according to any one of claims 1 to 6, which is for use as a medicament. A pharmaceutical composition according to any one of claims 1 to 7 for use in the treatment of allergy. A method of preparing a pharmaceutical composition according to any one of claims 1 to 8, which comprises The following steps: i) mixing phenoxyphenidine or its pharmaceutically acceptable salts, pharmaceutical excipients, glycerin and water, ii) adding high (methyl) pectin after heating, iii) adding, if used, adding a sugar, flavoring and/or coloring agent, iv) heating the resulting mixture of step (ii) to a temperature ranging from 60 ° C to 90 ° C, v) adjusting the pH with an acid, vi) forming and cooling the composition until Gelation occurred. The method of claim 9, wherein the step (i) is carried out as follows: a) mixing the phenoxyphenidine or a pharmaceutically acceptable salt thereof and the pharmaceutical excipient with water, b) the glycerin and the surface active The agent is added to the resulting mixture of step (a). The method of claim 10, wherein the step (a) is carried out by first mixing the pharmaceutical excipient with a portion of water to obtain a mixture having a paste-like consistency; and the phenoxyphenidine or a pharmaceutically acceptable salt thereof A portion is added to the mixture having a paste consistency, and then another portion of water is added; finally, the remainder of the phenoxyphenidine or a pharmaceutically acceptable salt thereof is added, and then the remaining water is added. The method of claim 9, wherein the step (i) is carried out as follows: I. mixing the water with the glycerin, II. adding the phenoxyphenidine or a pharmaceutically acceptable salt thereof and the pharmaceutical excipient to the In the mixture. The method of claim 12, wherein in step (II), the phenoxyphenidine or a pharmaceutically acceptable salt thereof and the pharmaceutical excipient are added to the mixture in powder form. The powder comprises the phenoxyphenidine or a pharmaceutically acceptable salt thereof in combination with the pharmaceutical excipient.