JP2000119198A - Phosphodiesterase inhibitor-containing peroral preparation hiding bitterness or the like - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject preparation masking a discomfortable taste such as bitterness of a cyclic guanosine 5'-monophosphate(GMP) phosphodiesterase inhibitor, excellent in drinking property and greatly contributing increase of compliance of a patient by including an anionic polymer substance. SOLUTION: This preparation contains (A) a cyclic GMP phosphodiesterase inhibitor having a discomfortable taste and (B) an anionic polymer substance (preferably carrageenan, chondroitin sulfate, dextran sulfate, alginic acid, gellan gum, xanthane gum and its salt). Preferably, the component A is sildenaphyll and concretely, 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxypiperidino) phthalazine chloride, etc., and 1-200 pts.wt. of the component B is mixed with 1 pt.wt. of the component A.

Description

DETAILED DESCRIPTION OF THE INVENTION

[Detailed Description of the Invention]

[0002]

The present invention relates to a cyclic GM
The present invention relates to an oral preparation containing a P phosphodiesterase inhibitor and masking an unpleasant taste such as a bitter taste.

[0003]

BACKGROUND OF THE INVENTION Cyclic GMP phosphodiesterase. It has been shown that pyrazonopyrimidinone compounds, which are basic drugs having a type V inhibitory action, are useful for the treatment of erectile dysfunction by oral administration.
No. is reported in the publication. Also, 5- [2-ethoxy-5- (4-methyl-1) represented by the formula (I) belonging to the class
-Piperazinylsulfonyl) phenyl] -1-methyl-3-
n-propyl-1,6-dihydro-7H-pyrazolo [4,3-
d] Pyrimidin-7-one {generic name: sildenafil}
Shows that pharmacological efficacy of papaverine hydrochloride and prostaglandin E1 conventionally used in urology is ensured for at least 2 hours even when administered orally (British. J. Urology, 78, 257-261 (1996)). It is highly likely that it will be a highly practical drug therapy for erectile dysfunction that replaces injection therapy into the corpus cavernosum. In addition, cyclic GMP phosphodiesterase. As a compound having a type V inhibitory action, a phthalazine derivative represented by the general formula (I) is also useful as a therapeutic drug for erectile dysfunction. The number of potential patients with erectile dysfunction is said to be about 3 million in Japan and about 20 million in the United States. In the United States, erectile dysfunction patients account for only 2-7% of the male population by the age of 50, but this percentage increases with age, with 15% of males in their 50s and 60% of males in their 60s. More than 30% are reported to fall under this disease. Most of them are caused by organic disorders, and with the coming of an aging society in the future,
It can be said that oral preparations of cyclic GMP phosphodiesterase inhibitors play an extremely important role in improving the quality of life (QOL) of patients with erectile dysfunction. However, many cyclic GMP phosphodiesterase inhibitors have an unpleasant taste such as bitterness, including sildenafil. Therefore, for such elderly people than healthy adults, erectile dysfunction therapeutic preparations that are easy to take and easy to drink with a masked unpleasant taste such as bitterness,
It greatly contributes to the improvement of QOL, and there is an extremely high demand. Many techniques have already been developed for masking the taste of a drug having an unpleasant taste. For example, a method of coating a granule with a water-soluble film (Japanese Patent Application Laid-Open No. 4-282212), a melting point of 40 ° C. to 100 ° C. A method of melting powdery waxes, dispersing a drug exhibiting an unpleasant flavor therein, and solidifying to obtain a powder or the like (JP-A-7-267).
No. 850) is known. On the other hand, in the case of liquid preparations, it is known that oral liquid preparations such as syrups are used to improve the feeling of ingestion, and they are widely used as dosage forms suitable for children, the elderly, etc. It is often difficult to completely conceal a syrup simply by the effect of the sweetener in the syrup. JP-A-4-346937 discloses a method of reducing bitterness by adding a gelling agent and a flavoring agent selected from agar, gelatin or κ-carrageenan to a substance having a bitter taste to form a flavored jelly. A method for reducing bitter taste is disclosed. This method reduces the contact of bitter substances to the tongue by making it jelly-like,
Partially soluble bitter substances are those whose bitterness is masked by the flavoring agent. However, the above-mentioned method has many problems, such as an insufficient unpleasant taste masking effect and an excessively complicated manufacturing process. Therefore, further techniques for applying to cyclic GMP phosphodiesterase inhibitors are required. Development is required.

[0004]

The development of a cyclic GMP phosphodiesterase inhibitor, which has an unpleasant taste such as a bitter taste and a large unpleasant taste, and a method for producing the same, is required. Oral formulations with satisfactory effects have not yet been developed.

[0005]

DISCLOSURE OF THE INVENTION The present invention is an oral preparation comprising a cyclic GMP phosphodiesterase inhibitor having an unpleasant taste and an anionic macromolecular substance, which masks the unpleasant taste. The anionic polymer substances shown here are carrageenan, chondroitin sulfate, dextran sulfate, alginic acid, gellan gum and xanthan gum and salts thereof, and phosphodiesterase inhibitors having an unpleasant taste include, for example, sildenafil and general The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. Further, the present invention is a method for masking unpleasant taste, which comprises mixing an anionic polymer substance with a cyclic GMP phosphodiesterase inhibitor having unpleasant taste. Further, the present invention provides an oral preparation containing a cyclic GMP phosphodiesterase inhibitor having an unpleasant taste and an anionic polymer, wherein the substance that masks the unpleasant taste is an anionic polymer. It is a taste masking agent.

The cyclic GMP phosphodiesterase inhibitor having an unpleasant taste according to the present invention is a drug having an effect of improving erectile dysfunction, for example, sildenafil, a compound represented by the general formula (I) or a pharmacology thereof. And pharmaceutically acceptable salts. In addition, the general formula (I)
The phthalazine derivative represented by, for example, is represented by the formula (IV)
4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1- (4-hydroxypiperidino) phthalazine hydrochloride represented by the formula: and 4- (3-chloro-methoxy-phthalazine hydrochloride represented by the formula (V)
Examples thereof include 4-methoxyphenethyl) amino-6-cyano-1- (4-hydroxypiperidino) phthalazine hydrochloride, and both compounds can be produced by the method described in JP-A-8-225541. However, the cyclic GMP phosphodiesterase inhibitor having an unpleasant taste in the present invention is not limited to these compounds.

In the present invention, the anionic polymer substance is not particularly limited, but an acidic polysaccharide is preferable, and specific examples thereof include carrageenan, chondroitin sulfate, dextran sulfate, alginic acid, gellan gum, xanthan gum and salts thereof. it can. For carrageenan, types such as κ, ι, and λ are known, and any of them can be used. Commercially available carrageenan can be used, for example, FMC Corporati
on: USA), Systems Bioindustry (Syste
ms Bio Industries Co., Ltd.).

[0008] The dosage form of the oral pharmaceutical composition of the present invention is
Solid, liquid or jelly means a dosage form taken orally. Specific examples of solids include granules, fine granules, powders, tablets, pills and the like. Specific examples include syrups, elixirs, emulsions, suspensions and the like, and particularly preferred are granules, fine granules, powders, syrups and jellies.

[0009] The concentration of the cyclic GMP phosphodiesterase inhibitor in the oral solution which masks unpleasant taste is generally 0.1 to 500 mg / ml, preferably 0.5 to 100 mg / ml. When the drug is sildenafil, its concentration is preferably from 1 to 100 mg / ml. In the present invention, the mixing ratio of the cyclic GMP phosphodiesterase inhibitor and the anionic polymer substance is generally 1 to 200 parts by weight of the anionic polymer substance per 1 part by weight of the cyclic GMP phosphodiesterase inhibitor. Part, preferably 1
0 to 200 parts by weight. When the oral preparation according to the present invention is a solid preparation, an unpleasant taste masking effect can be obtained by uniformly mixing the cyclic GMP phosphodiesterase inhibitor and the anionic polymer substance. Further, a cyclic GMP phosphodiesterase inhibitor and an excipient are mixed, and an anionic polymer is separately dissolved in a solvent such as water, an organic solvent or a water-containing organic solvent, and if necessary, with another binder. By mixing, gradually adding and granulating, an unpleasant taste hiding effect can be obtained. In the present invention, the anionic polymer acts as a substance that masks the unpleasant taste such as the bitter taste of the cyclic GMP phosphodiesterase inhibitor.

The method for producing the oral liquid preparation according to the present invention is not particularly limited, and any method for producing a general oral liquid preparation may be used. For example, it can be produced by dissolving a cyclic GMP phosphodiesterase inhibitor and an anionic polymer substance in water or various buffered salt solutions. Further, sweeteners such as sucrose, xylitol, mannitol, glucose, aspartame and saccharin, and flavoring agents such as vanilla essence and apple flavor can also be added. In addition, the method for producing the oral solid preparation according to the present invention is not particularly limited, and may be a generally used method. For example, granules are prepared by mixing a cyclic GMP phosphodiesterase inhibitor and kappa-carrageenan with excipients such as lactose, mannitol, starch, crystalline cellulose, and disintegrants such as croscarmellose sodium, and adding hydroxypropyl cellulose. It can be manufactured by using a commonly used granulation apparatus while adding a solution in which a binder such as described above is dissolved.

[0011]

Industrial Applicability The oral preparation according to the present invention is characterized in that, in an oral preparation containing a cyclic GMP phosphodiesterase inhibitor having an unpleasant taste, an unpleasant taste such as bitterness and numbness peculiar to the drug is masked. It is excellent in taking properties and greatly contributes to improvement of patient compliance. In particular, since patients suffering from erectile dysfunction, which is a target disease of cyclic GMP phosphodiesterase inhibitors, are often elderly, the oral formulation according to the present invention plays an extremely important role in improving QOL of elderly. .

Test Example 1 A 1 mg / ml aqueous solution of sildenafil was prepared.
5 ml, 10 mg, 25 mg, 50 mg, 75 mg of κ-carrageenan, ι-carrageenan, and λ-carrageenan in ml
mg, 100 mg or 125 mg was dissolved. next,
Three healthy subjects (indicated by A, B and C in the table) contain about 1 ml of the dissolving solution in their mouth, and disperse the solution in the oral cavity while being careful not to swallow them. The degree of unpleasant taste was evaluated on a five-point scale. The evaluation was performed based on the following scores. 1: very bitter, 2: bitter, 3: slightly bitter, 4: bitter, 5: feel nothing The results are shown in Tables 1-3.

[0013]

[Table 1]

[0014]

[Table 2]

[0015]

[Table 3]

As is apparent from Tables 1 to 3, unpleasant tastes such as sildenafil bitterness were significantly suppressed by the addition of κ-carrageenan, ι-carrageenan and λ-carrageenan. Among the drugs belonging to the cyclic GMP phosphodiesterase inhibitors, the sildenafil taste is particularly bitter and irritating, but the unpleasant taste is significantly suppressed by the addition of carrageenan, an anionic polymer. Therefore, it is clear that the effect of the present invention is extremely excellent.

[0017]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

Example 1 Sildenafil 50 mg and saccharin sodium 20
0 mg and 7 g of polyvinylpyrrolidone were dissolved in 50 g of purified water, and 1500 mg of κ-carrageenan was separately dissolved in 5 g of purified water.
The mixture was heated to 80 ° C. and dissolved. After cooling, both were mixed, and a solution prepared by dissolving 200 mg of methylparaben and 15 mg of propylparaben in a small amount of propylene glycol was added to produce a syrup.

Example 2 Among the compounds represented by the general formula (I), 4- (3-chloro-4-methoxyphenethyl) amino represented by the formula (V)
10 mg of -6-cyano-1- (4-hydroxypiperidino) phthalazine hydrochloride, 50 mg of aspartame and 5 g of polyvinylpyrrolidone are dissolved in 100 g of purified water, and another 200 mg of io-carrageenan is added to 50 g of purified water.
Heated to ° C. to dissolve. After cooling, the two were mixed, and 200 mg of methylparaben and 15 mg of propylparaben were further added.
Was dissolved in a small amount of propylene glycol to prepare a syrup.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Takashi Kato 3-16-2 Azuma, Tsuruga-shi, Ibaraki 203 F-term (reference) 4C076 AA09 AA12 AA22 AA30 AA31 BB01 CC17 DD43 DD61 EE16 EE23 EE36T EE37T EE38T FF52 GG12 4C08A AA27 MA05 MA17 MA23 MA27 MA41 MA52 NA09 ZA811 ZA812 4C086 AA02 BC41 CB06 GA07 MA02 MA05 MA17 MA23 MA27 MA41 MA52 NA09 ZA81

Claims (9)

[Claims] 1. An oral preparation comprising a cyclic GMP phosphodiesterase inhibitor having an unpleasant taste and an anionic polymer substance, which masks the unpleasant taste. 2. The oral preparation according to claim 1, wherein the anionic polymer substance is carrageenan, chondroitin sulfate, dextran sulfate, alginic acid, gellan gum, xanthan gum and salts thereof. 3. The oral preparation according to claim 1, wherein the cyclic GMP phosphodiesterase inhibitor having an unpleasant taste is sildenafil. 4. The unpleasant taste according to claim 1, wherein the cyclic GMP phosphodiesterase inhibitor having an unpleasant taste is a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. Oral formulation concealed. Embedded image 中 In the formula (I), 1 means an integer of 1 to 3. X represents a cyano group, a nitro group or a halogen atom. Y ¹ is i) Formula (II) (In the formula (II), W represents an amino group, a cyano group or a lower alkoxy group. M represents an integer of 4 to 6, and n represents 0 or an integer of 1 to 3.) ii) Formula (III) (In the formula (III), p is an integer of 4 to 6, q and r are the same or different and each represents an integer of 0 or 1 to 3), iii) From the following substituent group A A phenyl group optionally substituted with 1 to 3 selected substituents, or iV) a pyridyl group or pyrimidyl group optionally substituted with 1 to 3 substituents selected from the following Substituent Group A , A thienyl group or a heteroaryl group which is a freel group. [Substituent group A] lower alkyl group optionally substituted with halogen atom, cyano group, nitro group or hydroxyl group; lower alkoxy group optionally substituted with halogen atom, cyano group, nitro group or hydroxyl group; cyano group A nitro group;
A carboxyl group which may have a protecting group; a hydroxyl group which may have a protecting group; a carbamoyl group which may be substituted by a lower alkyl group; Provided that when 1 is 1, m is 5, n is 0 and Z ′ is a methoxy group;
And p is 5 and p and q are both 0; and 1 is 1 and X
Is a chloro group and Y is a phenyl group substituted by a methoxy group. A phthalazine derivative or a pharmacologically acceptable salt thereof, or a hydrate thereof, 5. The oral composition according to claim 1, wherein the content of the cyclic GMP phosphodiesterase inhibitor having an unpleasant taste is 1 to 200 parts by weight with respect to 1 part by weight of the anionic polymer substance. Formulation. 6. A compound represented by the general formula (I) is converted to 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1- (4-hydroxypiperidinium represented by the following formula (IV): No) phthalazine hydrochloride or 4 represented by the formula (V)
The oral preparation according to claim 4, which is-(3-chloro-4-methoxyphenethyl) amino-6-cyano-1- (4-hydroxypiperidino) phthalazine hydrochloride. Embedded image Embedded image 7. An oral preparation comprising granules, fine granules, powders, liquids,
7. The oral preparation according to claim 1, which is a syrup or a jelly preparation. 8. A method for masking an unpleasant taste, comprising blending an anionic polymer substance with a cyclic GMP phosphodiesterase inhibitor having an unpleasant taste. 9. An oral preparation comprising a cyclic GMP phosphodiesterase inhibitor having an unpleasant taste and an anionic polymer, wherein the substance which masks the unpleasant taste is an anionic polymer. Concealing agent.