FR2486398A1 - COMPOSITION FOR PREPARATION WITH NO AMERTUME - Google Patents

Abstract

THE PURPOSE OF THE PRESENT INVENTION IS TO MASK THE BITNESS OF A WATER-SOLUBLE BITTER DRUG SUBSTANCE. IN ACCORDANCE WITH THE PRESENT INVENTION, TO THE COMPOSITION FOR PREPARATION CONSISTING OF A WATER-SOLUBLE BITTER DRUG SUBSTANCE AND A WAXY MATERIAL, A HIGH-WEIGHT MOLECULAR WATER-INFLATABLE MATERIAL IS ADDED TO THE COMPOSITION FOR PREPARATION. USE FOR PREPARATIONS BASED ON BITTER DRUG SUBSTANCES.

Description

Preparation composition without bitterness.

  The present invention relates to a composition for preparing

  which contains a soluble bitter drug substance

  with water but whose taste is not bitter and the invention

  also a process for the production of such a compound

  preparation. Since it is undesirable to administer a drug substance having a bitterness accentuated as it is, the drug substance is usually administered in a form in which the bitterness is sufficiently masked such as in the form of sugar-coated tablets, tablets coated with film, seals, etc. However, a composition based on such bitter drug substance in a form suitable for preparation in the form of powder, fine granules, granules, etc.,

  is intensely requested and different tests have been carried out

  made to hide the bitterness of these compositions. One of the main attempts is based on a method in which a composition for a preparation, such as a powder, is produced by melting a solid material having a melting point of about 40 to 100 ° C, by dispersing a drug substance having a bitterness accentuated in the molten material and then cooling and solidifying the dispersion by spraying it through a nozzle or

  alternatively by solidifying the dispersion by cooling

  in the state and subjecting it to grinding.

  However, when such a conventional composition pre-

  prepared by such a method is administered orally, the drug resists oral dissolution and, therefore, the composition can have excellent bitter masking effect, but it dissolves the drug substance in the mouth. food tract

  low, which translates into a reduction in the bioavailability

  bility of the medicinal substance. For example, British Pat. No. 1,323,161 discloses a process wherein particles of a bitter drug substance are coated with a mixture (having a melting point greater than 95 ° C) of more than 50% hardened castor oil and less than 50% of a fatty acid having more than 16 carbon atoms. However, the medicinal composition obtained may have an excellent effect of masking bitterness but presents a considerable difficulty with regard to the possibility of

  absorption of the drug substance.

  To overcome such a difficulty, it is conceivable to combine the waxy solid material with a water-soluble material having a melting point of 40 to 100WC (for example polyethylene glycol, a sucrose fatty acid ester having a high hydrophilic-lipophilic balance, etc.), but there is a difficulty in that such a water-soluble material does not mix uniformly with a waxy solid material even if they are mixed in the molten state. In addition, the combination of a water-soluble excipient such as

  lactose, mannitol, etc., is hardly effective for improving

  improvement of the defect described above.

  In these circumstances, the inventors have carried out various investigations to produce compositions for preparations, such as powders, fine granules, granules, etc., having excellent solubility and having no bitterness and, following these, Here, it has been discovered that a preparation composition having an excellent effect to mask the bitterness of a bitter drug substance and having a high degree of dissolution of the drug substance, is obtained by uniformly dispersing a drug substance soluble in the drug. water having a marked bitterness in a molten waxy material by adding to it a water-swellable high molecular weight material and finely granulating the mixture and

high rate of dissolution.

  It is therefore an object of the present invention to provide a preparation composition which contains a water-soluble bitter drug substance whose taste is not

not bitter.

  Another object of the present invention is to provide a method of

  of producing such a composition for preparation.

  Namely, the subject of the present invention is a non-bitterness preparation composition comprising a water-soluble bitter drug substance, a waxy material and an inflatable high molecular weight material.

at the water.

  In addition, in accordance with another embodiment of the

  The subject of the present invention is a method of

  production of a preparation composition which does not

  no bitterness which consists in dispersing a medicinal substance

  bitter, water-soluble camerose in a melted waxy material, together with a high molecular weight material

  inflatable with water and then solidifying the dispersion.

  The medicinal substances used in the composition of the present invention are those soluble in water having

  a marked bitterness but there is no particular restriction

  the types of substances and the degree of bitterness. Practical examples of these drug substances are talampicillin hydrochloride which

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  is an antibiotic, indenolol hydrochloride which is

  an a-blocker, hydralazine hydrochloride which is an

  depressed, chloropromazine hydrochloride which is a tranquilizer, etc. Examples of waxy materials used in the present invention are waxes such as carnauba wax, beeswax, etc .; solid fats and oils such as hydrogenated castor oil, acetylated lemon glyceride, etc., higher fatty acids such as stearic acid, palmitic acid, etc .; and higher alcohols such as cetyl alcohol, stearyl alcohol, etc. In the present invention the use of high materials

  water-inflatable molecular weight is the characteristic

  Examples of these materials are hydroxypropyl-

  cellulose with a low degree of substitution (L-HPC),

  carboxymethyl cellulose or a calcium salt thereof

  ci, crosslinked polyvinylpyrrolidone (PVPP), ion exchange resins used for drugs, etc. The composition for the preparation of the present invention

  consists of a combined mixture of the drug substance

  bitter liar with one or more waxy materials and one or more high molecular weight inflatable materials

at the water.

  The preparation composition of the present invention is produced by dispersing a bitter drug substance and a water-swellable high molecular weight material in a waxy waxy material and then solidifying by spray-cooling the dispersion through a nozzle or solidifying by cooling the dispersion in the state and grinding it into fine granules by means of a

mill.

  The suitable level of combination of each of the components of the preparation composition of the present invention is that the proportion of the waxy material is greater than three parts (by weight) for a portion of the drug substance and the high molecular weight inflatable material. water represents 0.05 to 0.3 part for a part of the waxy material. If the waxy material combination rate is lower, the viscosity of the dispersion obtained by dispersing the drug substance and the high molecular weight material in the molten waxy material becomes high, making it difficult to obtain fine granules or particles by spraying the dispersion and, from

  to obtain well-coated granules or particles.

  Similarly, if the composition ratio of the high molecular weight material is lower, the blowing power and the dissolving effect become insufficient while, if the

  combination rate is too high, the viscosity of the

  persion becomes high and, as a result, becomes difficult

  to prepare granules or fine particles.

  Various preparations have been produced using the preparation composition of the present invention by adding a conventional excipient for the preparation such as lactose, mannitol, etc., and, if necessary, other ingredients such as coloring agents, perfumes, etc., but these preparations can be produced also

  adding the component mentioned above during the pro-

production of preparations.

  Then, to show the effects of the composition for preparing the present invention, the organoleptic test results for bitterness and dissolution test results are given in Table 1 together.

  with the results of comparison samples.

Table I

  Test sample Result Dissolution test result (%) Example Substance Material Material at organoleptic test report 30 min. 60 min. 90 min. Waxy Drug High-Weight Molecular Weight .... Comparison I Talampicillin Hydrochloride Il fi Il Il Il Comparison 2 Hydralazine Hydrochloride

7 'T

  Comparison Chloropromazine hydrochloride I! Lubriwax It is l Himako Lubriwax l l l l l 1: 4 L-HPC L-HPC CMC Ca Amberite PVPP L-HPC L-HPC CMC Ca L-HPC L-HPC

1: 3: 0.25

1: 4: 0.5

1: 4: 0.5

1: 4: 0.5

  1: 5: 1 1: 5: 1 1: 5 1: 5: 1 1: 5: 1 1: 5 1: 5: 1 I: 5, 1; 5: 1 (-) (-) (-) ( -) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) 11.6 82.9 92.1 91.5 89.4 96, 3, 3, 2, 83, 81.8, 11.6, 2.0, 87.9, 12.1, 4 96.4, 96.3, 93.8, 98.5, 93.4, 6.9, and 84.5; 7 87, 2 36,, 7, 5 13.5 88.1 96.8 97.2 94.3 98.2 94.1 7.9 87.1 87.7 17.3 89.3 34, 8 96 , 6 ro) o o0 Co Note: (1) In the organoleptic test (-) means that no

  Bitterness was not perceived to taste.

  (2) The measurement of the dissolution was carried out by adding

  both 100 mg of the fine granules of the sample in a 100 milliliter flask containing 50-ml of the "first liquid" of the Japanese Pharmacopoeia at 37 + 0.5 C, shaking the flask in a constant-temperature bath with an amplitude 3.5 cm and a frequency of 120 shakes per minute and then measuring the substance

  medicinal product thus dissolved by an absorption method

  tiométrie. (3) Comparative samples 1, 2, 3 and 4 were produced following the same method as in Example

1.

  The results indicated in the Table above show that the preparation composition of the present invention gives no bitter taste to the organoleptic test and that at the same time it has an excellent dissolution rate.

  by comparison with the comparison compositions.

  The compositions of the present invention and their methods of production are explained in more detail in the examples

following.

EXAMPLE 1

  In 300 g of hydrogenated vegetable oil (trademark "Lubriwax 102H" manufactured by Freund Industries Co., Ltd.) melted at

  oil bath were uniformly dispersed 100 g of chlorhydrin.

  talampicillin drate and 25 g of L-hydroxypropylcellulose (brand "LHPC" manufactured by Shin-Etsu Chemical Co., Ltd.) and then the dispersion was sprayed in an enclosure, at temperatures below 30 C, using an atomizer of the rotary disk type (manufactured by Iwai Kikai Kogyo KK) to provide screened granules passing through a screen of 0.55

at 0.20 mm of mesh opening.

EXAMPLE 2

  Talampicillin hydrochloride 100 g Hydrogenated vegetable oil (Lubriwax 102H) 400 g L-hydroxypropylcellulose (L-HPC) 50 g

  Coated pellets were produced using

  above in the same way as in Example 1.

EXAMPLE 3

  Talampicillin hydrochloride 100 g Hydrogenated vegetable oil (Lubriwax 102H) 400 g Calcium salt of carboxymethylcellulose (Brand "ECG 505", manufactured by Gotoku Yakuhin Kogyo KK) 50 g The coated granules were produced using the above components of the same way as in Example 1.

EXAMPLE 4

  Talampicillin hydrochloride 100 g Hydrogenated vegetable oil (Lubriwax 102H) 400 g Ion exchange resin (Brand "Amberlite IRP-88", manufactured by Rhom and Haas Co.) 50 g

  Coated granules have been produced using

  above in the same way as in Example 1.

EXAMPLE 5

  Talampicillin hydrochloride 100 g Hydrogenated vegetable oil (Lubriwax 102H) 500 g Crosslinked polyvinylpyrrolidone ("Kollidon CL" brand, manufactured by BASF AG) 100 g Coated granules were produced using the above components in the same manner as in Example 1

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EXAMPLE 6

  Talampicillin Hydrochloride 100 g Hydrogenated vegetable oil (Brand "Hima KO", manufactured by Kawaken Fine Chemical Co., Ltd.) 100 g

  Coated granules were produced using the

  above in the same way as in Example 1.

EXAMPLE 7

  Hydralazine hydrochloride 100 g Hydrogenated vegetable oil (Lubriwax 102H) 500 g Hydroxypropylcellulose (L-HPC) 100 g

  Coated granules have been produced using

  above in the same way as in Example 1.

EXAMPLE 8

  Hydalazine hydrochloride 100 g Hydrogenated vegetable oil (Lubriwax 102H) 500 g Calcium salt of carboxymethyl cellulose (ECG 505) 100 g

  Coated granules have been produced using

  above in the same way as in Example 1.

EXAMPLE 9

  Indenolol hydrochloride 100 g Hydrogenated vegetable oil (Lubriwax 102H) 500 g Hydroxypropylcellulose (L-HPC) 100 g

EXAMPLE 10

  Chloropromazine hydrochloride - 100 g Hydrogenated vegetable oil (Lubriwax 102H) 500 g Hydroxypropylcellulose (L-HPC) 100 g

  Coated granules have been produced using

  above in the same way as in Example 1.

1 \

Claims (6)

claims   1. A composition for preparation having no bitterness comprising a bitter drug substance soluble in water and a waxy material,   characterized in that it further comprises a material   high molecular weight inflatable with water.   2. A composition for preparation according to claim 1, characterized in that the proportion of the waxy material is greater than three parts by weight for a part of the water-soluble bitter drug substance and that the proportion of material at high water-swellable molecular weight corresponds to 0.05 to 0.3 parts by weight for a part of the waxy material.   3. A composition for preparation according to any one claims 1 or 2,   characterized in that the waxy material is at least one member selected from waxes, solid fats and oils, higher fatty acids and higher alcohols and in that the high molecular weight water-swellable material is selected hydroxypropylcellulose with a low degree of substitution, carboxymethylcellulose,   of calcium from carboxymethylcellulose, polyvinylpyridine   crosslinked rolidone and the ion exchange resins   cinales. 4. A preparation composition according to any one of Claims 1 to 3,   characterized in that the bitter drug substance   soluble in water is talampicillin hydrochloride.   5. A composition for preparation according to any one of 2 Claims 1 to 3,   characterized in that the water-swellable high molecular weight material is low-hydroxypropylcellulose degree of substitution.   A process for producing a bitterless preparation composition characterized by dispersing a water-soluble bitter drug substance in a waxy waxy material together with an inflatable high molecular weight material at the water and then solidifies the dispersion.