KR20050034619A - New dry and aqueous epinastine-syrup-formulation - Google Patents

Abstract

The present invention refers to a new formulation of epinastine in form of a powder (dry syrup) to be mixed with water prior to use. Epinastine can be used either as free base or as a pharmaceutically acceptable salt thereof. Epinastine among others is for treating allergies, pain, in particular chronic pain and inflammation caused pain, migraine, asthma, rhinitis, conjunctivitis and/or bronchitis. In particular, the formulation is for treating allergies, dermatitis, rhinitis, conjunctivitis, bronchitis and asthma.

Description

New dry and aqueous epinastine-syrup-formulation

The present invention relates to a novel efinastin formulation in the form of a powder (anhydrous syrup) which is mixed with water before use. Among them, efinastin is allergic, pain, in particular chronic and inflammation-induced pain, migraine, asthma, rhinitis, conjunctivitis and / or bronchitis [European Patent Publication No. 0 035 749, European Patent Publication No. 1 000 623] To cure. In particular, the formulation is for the treatment of allergies, dermatitis, rhinitis, conjunctivitis, bronchitis and asthma.

Aspects of the art

Epineast and its acid addition salts, known by the chemical name 3-amino-9,13b-dihydro-1H-dibenz- [c, f] imidazo [1,5-a] azepine, are described in European Patent Publications. First described in German Patent Application No. P 30 08 944.2, which forms the basis of 0 035 749.

The chemical name efinastin is represented by the following formula, which does not exhibit stereochemical properties:

Epinastine can be used as the free base or a pharmaceutically acceptable salt thereof. Preferably, efinastin is used as the hydrochloride salt.

Unless further characterized in the context of the present invention, the term efinastin is used in the free base as well as pharmaceutically acceptable salts.

Processes for the preparation of efinastin can be cited in European Patent Publication No. 0 496 306 or WO 01/40229.

Epineast is marketed in Japan under the trade name Alesion ^R and most are used because of its antihistamine effect.

Embodiments in the art prefer tablets as an application form of efinastin.

However, especially for children or adults, tablets are not easy to take and there is a need for new formulations that are easily administered to children or adults.

Summary of the invention

Formulations suitable for this group of consumers, such as children and adults, have been found to be liquid formulations. However, it has been shown that efinastin has a very bitter taste.

As a result, there is a need to develop a liquid formulation of neutral or good taste in one of efinastin and / or pharmaceutically acceptable acid addition salts thereof, i.e. one solution of the present invention.

It is yet another object of the present invention to provide a liquid efinastin formulation which can be preserved for several hours without the risk of rapidly degrading drug quality.

Yet another object of the present invention is to prepare the efinastin formulations easily for handling so that they can be provided as a liquid. Such liquid formulations should also be in solution rather than dispersion to improve their water solubility to the patient.

Detailed description of the invention

The present invention relates to a powdered formulation (anhydrous syrup) of efinastin in enantiomeric, racemic form or salts thereof, which is mixed with water before use. To do this, it is necessary for the powder to dissolve very quickly in water.

In the context of the present invention, the term "powder" refers to an essentially water-free mixture in the active form of efinastin, preferably efinastin hydrochloride, and an aqueous sweet taste formulation of the active substance when mixed with water. It is used simultaneously with the term "anhydrous syrup", which in turn indicates the required pharmaceutically acceptable additive and adjuvant.

Surprisingly, it has been found that aqueous formulations of efinastin hydrochloride result in an unpleasant taste of two different kinds of very bitter form. On the one hand, it has a fast-acting bitter taste, and on the other hand, it has a slow-fat bitter taste that tastes for quite a long time.

Unfortunately, the bitter taste of efinastin cannot be blocked by using one conventional taste blocker, for example sucrose.

Instead, it has been found that strong bitterness can be overcome by a combination of fast-acting and slow-release sweeteners and flavors.

As a result, preferred embodiments of the formulations of the invention should include one or more of these various blockers.

To block the fast-acting bitterness, saccharin sodium, erythritol and / or aspartame have been shown to be effective. Another suitable group of compounds includes sugars and sugar derived polyols such as sucrose, D-sorbitol, glycerin and D-mannitol. Preferably, the formulation comprises sodium saccharin, erythritol and / or aspartame. Most preferred is a combination of saccharin sodium, erythritol and aspartame.

The amount of one or more blockers to block sustained bitterness depends on the formulation used. For saccharin sodium, it is from 0.1 to 2.0% w / w of the powder formulation. Preferably it is 0.8 weight / weight%.

In the case of erythritol, 50 to 95% w / w of the powder formulation. Preferably, it is 75 to 80% by weight, most preferably 80% by weight.

In the case of aspartame, it is 1 to 30% w / w of the powder formulation. Preferably, it is 5 to 15% by weight, most preferably 10% by weight.

In order to block the sustained bitterness, glycyrizine has been found to be very effective. Among these, glycyric acid and / or monoammonium glycyrizinate is preferable. Most preferred are monoammonium glycyrizinates.

The amount of monoammonium glycyrizinate in the powder formulation is 0.1-3.0% w / w of the powder formulation. 0.1-1 weight / weight% is more preferable, 0.6 weight / weight% is the most preferable.

The formulation may further comprise an adjuvant, of which, for example, pH adjusters. It is preferable to add such a pH adjuster so that the pH of the liquid obtained is adjusted to 5-8, preferably 6-7. Among these preparations are citric acid, succinic acid, tartaric acid, acetic acid, citrate, acetate, vitamin C, hydrochloric acid, carbonate, phosphate, disodium phosphate, monosodium phosphate, sodium-, calcium-, potassium- and / or magnesium hydroxide There is. Preferred are buffer substances such as disodium phosphate.

In addition, additives commonly used otherwise may be optionally added. Among these,

Binders, for example hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, starch, dextrin, gelatin and polyvinylpyrrolidone, preferably hydroxypropylcellulose,

Glidants, for example hydrated silicon dioxide, dilute anhydrous silicic acid,

Fragrances, such as sunfix orange No. 22734 (trade name, preferably including orange flavor (30% w / w), acacia (30% w / w) and dextrin (40% w / w)), orange oil, meta oil, eucalyptus strawberry flavor, Vanilla flavor, yogurt flavor and other flavors known in the art,

Pigments such as food coloring yellow pigments No. 5 (also known as sunset yellow FCF (disodium salt of 6-hydroxy-5- (4-sulfophenylazo) -2-naphthalenesulfonic acid), the latter being preferred), iron oxide and others Food coloring, fe Edible Red Pigment No. 3, 102, 105 and 106 as known dyes in Japan, food yellow pigment No. 4 and other food colorings known in the art and / or

Preservatives, for example benzoic acid, salts thereof, preferably sodium benzoate, paraoxybenzoic acid, salts thereof and other known preservatives, preferably sodium benzoate and

Foaming agents, for example bicarbonates.

The amount of efinastin or salt thereof is from 0.5 to 5% w / w of the powder formulation. More preferably 0.5 to 2% w / w, most preferably 1% w / w.

Powder formulations preferably do not comprise an active substance other than efinastin or a pharmaceutically acceptable salt thereof.

The active substance, preferably efinastin hydrochloride and all other additives are mixed into the powder and the powder is mixed with water to obtain a liquid formulation preferably. Although the liquid formulation may be a solution, suspension or colloid, the preferred liquid formulation is a clear and clear aqueous solution.

It is preferred to mix the powder formulation with water to obtain a liquid having a concentration of 250 mg per 5-50 ml to 2,000 mg per 10-100 ml, preferably 50 mg per 10 ml to 2,000 mg per 10 ml.

To ensure that the patient can easily prepare a liquid formulation, the powder formulation (anhydrous syrup) of the present invention can be delivered in a specific package. In this package water and the powder formulation of the invention are stored separately from each other. The package further mixes the two components in an easy manner.

The present invention therefore also relates to a kit comprising two components separated from one another, the powder formulation (a) and water (b) of the invention.

In an aspect of the art, several bottles with specific caps are known to solve this problem. Often in such packages the liquid solvent is stored in glass bottles, plastic bottles, metal bottles and the like, and the cap for sealing the bottle may comprise a chamber containing anhydrous powder formulation. Prior to use, the patient may take the powder in a cap and mix it with the water in the bottle. This mixing process can be performed consciously, which means that the patient actively takes the powder and places it in water. In another embodiment, the patient may be in a more automated manner, for example, by appropriately screwing, pressing, shaking and then dropping the cap or bottle into the bottle to remove the barrier in the chamber containing the powder. The mixing process can be started.

Such a package is, for example, European Patent Publication No. 0 599 189, European Patent Publication No. 0 344 849, European Patent Publication No. 0 217 425, European Patent Publication No. 0 093 090, US Patent No. 3 802 604 And the like. As such, all these devices are incorporated by reference. Alternatively, similar devices can be used. On the other hand, such a package is formed so that the anhydrous syrup formulation can be stored in an aluminum or plastic bag or an aluminum or plastic bottle. This stored powder may be used with a pre-weighed amount of water, stored in another package, or freshly filled beverages.

Other package systems can also be used.

In the context of the present invention, powder formulations can also be pressed into tablets, such as bubble tablets, which are dissolved in water. In such embodiments, tablets, such as powder formulations, may further comprise a foaming agent, such as bicarbonate.

Experiment

New Anhydrous and Aqueous Epineast Syrup Formulation 0.5%. Powder Formulation No. One 2 3 4 5 6 7 Epineast Hydrochloride [mg] 5 5 5 5 5 5 5 Glycerin [mg] 0 0 0 0 0 0 350 Sucrose [mg] 0 0 0 0 0 540 620 Citric anhydride [mg] 0 0 0 0 0 25 0 Monoammonium Glycyrizinate [mg] 7 0 6 6 6 0 0 Saccharin Sodium [mg] 0 6 4 0 5 5 0 Sodium Fumarate [mg] 10 10 0 10 5 0 10 Disodium phosphate [mg] 0 0 0 3 15 10 0 Erythritol [mg] 923 919 925 916 904 395 0 Aspartame [mg] 60 60 60 60 60 25 0 Sodium benzoate [mg] 0 0 0 0 0 0 15 result Appearance when mixed with water White Transparent ^# White Transparent ^# Transparent ^# Transparent ^# Transparent ^# Bitter Taste Blocking Good Good Good Good Very good Good Good

^* The amount of water is not important. However, 1 g of powder should preferably be easily dissolved in 5 to 50 ml of water.

^# Transparency means sunny.

New Anhydrous and Aqueous Epineast Syrup Formulation 1.0%. Powder Formulation No. 8 9 10 11 12 13 14 Epineast Hydrochloride [mg] 10 10 10 10 10 10 10 Glycerin [mg] 0 0 0 0 0 0 350 Sucrose [mg] 0 0 0 0 0 542 425 Citric anhydride [mg] 0 0 0 0 0 25 0 Monoammonium Glycyrizinate [mg] 10 0 10 6 6 0 0 Saccharin Sodium [mg] 0 10 5 0 8 0 0 Sodium Fumarate [mg] 20 10 0 15 5 0 10 Disodium phosphate [mg] 0 0 0 10 15 0 0 Erythritol [mg] 859 859 854 838 835 397 200 Aspartame [mg] 100 100 100 100 100 25 0 Hydroxypropyl cellulose [mg] 0 20 20 20 20 0 0 Hydrated Silicon Dioxide [mg] One One One One One One 0 Fragrance ^* [mg] 0 (One) (One) (One) (One) (One) 0 Edible Yellow Pigment No.5 ^** [mg] 0 (0.05) (0.05) (0.05) (0.05) (0.05) 0 Sodium benzoate [mg] 0 0 0 0 0 0 5 result Appearance when mixed with water White Transparent ^# White Transparent ^# Transparent ^# Transparent ^# Transparent ^# Bitter Taste Blocking Good Good Good Good Very good Good Good

^* Sunpix Orange No. 22734 ™ contains orange flavor (30% by weight), acacia (30% by weight) and dextrin (40% by weight).

^** Food Yellow Pigment No. 5 is sunset yellow FCF (disodium salt of 6-hydroxy-5- (4-sulfophenylazo) -2-naphthalenesulfonic acid).

^*** The amount of water is not critical, but 1 g of powder should preferably be easily dissolved in 10 to 100 ml of water.

^# Transparency means sunny.

Claims (26)

Two or more sweetening agents, and / or active agents based on efinastin and / or acid addition salts, preferably hydrochloride, two or more sweetening and / or flavoring agents, and optionally additional pharmaceutically acceptable auxiliaries, and / or Or one of the flavoring agents for blocking the fast-acting bitter taste of the active agent, and the other for blocking the slow-acting bitter taste of the active agent. The method of claim 1, wherein the one or more sweetening and / or flavoring agents to block the fast-acting bitter taste are saccharin sodium, erythritol, aspartame and / or sugars, or other such as sucrose, glycerin, D-sorbitol and D-mannitol. Pharmaceutical powder formulation, characterized in that it is selected from polyols. 3. The pharmaceutical powder formulation of claim 1, wherein at least one sweetening and / or flavoring agent for blocking the fast-acting bitter taste is selected from saccharin sodium, erythritol and aspartame. 4. The pharmaceutical powder formulation of claim 1, wherein the one or more sweetening and / or flavoring agents for blocking the fast-acting bitter taste is a combination of saccharin sodium, erythritol and aspartame. 5. The method of claim 1, wherein the one or more sweetening and / or flavoring agents for blocking sustained bitter taste are preferably mono-, diammonium glycyrizinate, disodium-, trisodium glycyrinate and And / or a glycyrrhinate or glycyric acid selected from dipotassium glycyrizinate, most preferably monoammonium glycyrizinate. 6. Citric acid, citrate, succinic acid, tartaric acid, acetic acid, acetate, vitamin C, hydrochloric acid, carbonate, sodium-, calcium-, potassium- and / or magnesium hydroxide according to any one of claims 1 to 5. , A pH-adjusting agent selected from the group consisting of phosphates, preferably disodium phosphate and / or monosodium phosphate, most preferably monosodium phosphate. 7. The pharmaceutical powder formulation of claim 1, further comprising one or more adjuvants selected from the group consisting of fragrances, colorants, preservatives, flow agents and / or binders. The method according to any one of claims 1 to 7, wherein 0.5 to 5% by weight efinastin hydrochloride, 0.1 to 2.0% by weight saccharin sodium, 50 to 95% by weight erythritol, aspartame 1 To 30% w / w, monoammonium glycyrizinate 0.1 to 3.0% w / w, and optionally disodium phosphate, sodium fumarate, hydroxypropylcellulose, hydrated silicon dioxide, orange flavor, acacia, dextrin and / or 6 A disodium salt of hydroxyl-5- (4-sulfophenylazo) -2-naphthalenesulfonic acid. 9. The process of claim 1, wherein efinastin hydrochloride, monoammonium glycyrinate, saccharin sodium, sodium fumarate, erythritol, aspartame, hydroxypropylcellulose, hydrated silicon dioxide, orange A pharmaceutical powder formulation, comprising a disodium salt of aroma, acacia, dextrin and 6-hydroxyl-5- (4-sulfophenylazo) -2-naphthalenesulfonic acid. The pharmaceutical powder formulation of any one of claims 1 to 9, characterized in that it comprises a foaming agent. A pharmaceutical tablet comprising the components of a powder formulation according to any one of claims 1 to 10. A liquid formulation obtained by mixing water with either the powder formulation according to claim 1 or the tablet according to claim 11. 13. The liquid formulation of claim 12, which is a solution. The liquid formulation of claim 13, which is a dispersion. 14. A liquid formulation according to claim 12 or 13, characterized in that it comprises the pH adjusting agent according to claim 6 in an amount in which the pH is adjusted to 5-8, preferably 6-7. The liquid formulation according to any one of claims 12 to 15, characterized in that the amount of efinastin is from 0.09 to 35 mg, preferably 0.4 to 18 mg per 10 ml. 16. Liquid formulation according to claim 12, characterized in that the amount of epinastine hydrochloride is 0.1-40 mg, preferably 0.5-20 mg per 10 ml. The powder formulation according to claim 12, wherein the powder formulation according to any one of claims 1 to 9 or 250 to 2,000 mg or the tablet according to claim 11 is mixed with 10 to 100 ml of water. Liquid formulation. 19. A kit comprising a powder formulation according to claim 1 or a tablet according to claim 11, wherein when the powder and water are mixed together, the water is separated to thereby separate any of claims 12 to 18. A package, characterized in that it obtains a liquid formulation according to claim 1. The chamber of claim 19, wherein the cap comprises a powder formulation according to claim 1 or a tablet according to claim 11, which can be screwed or pressed onto the bottle or easily opened manually. The package, characterized in that the cap is equipped with a bottle containing water. Use of a powder formulation according to any one of claims 1 to 10 or a tablet according to claim 11 for mixing with water to obtain a formulation according to any one of claims 12 to 18. According to any one of claims 1 to 18 for the manufacture of a medical preparation for allergy, pain, in particular chronic pain and inflammation-induced pain, migraine, asthma, rhinitis, conjunctivitis and / or bronchitis, preferably allergy Use of the formulation. The powder formulation according to any one of claims 1 to 10 or the tablet according to claim 11 are mixed with water to obtain a liquid formulation according to any one of claims 12 to 18, which is administered to the patient. Characterized in that allergy, pain, in particular chronic and inflammation-induced pain, migraine, asthma, rhinitis, conjunctivitis and / or bronchitis, preferably allergy. A process for preparing a powder formulation according to any one of claims 1 to 10 by mixing different components together. A method according to claim 11, wherein the different ingredients are mixed together and subsequently pressed to make them. A process for preparing a liquid formulation according to any one of claims 12 to 18 by mixing the powder formulation according to any one of claims 1 to 10 or the tablet according to claim 11 with water.