JPH05279245A - Sustained release suspension pharmaceutical having stable release property - Google Patents

Abstract

PURPOSE:To obtain a sustained release aqueous suspension pharmaceutical having stable release properties of a medicine for a long period just after its production. CONSTITUTION:The release properties of a medicine are stabilized by supporting an amino acid, preferably glutamic acid, glycine, alanine, lysine, histidine or a salt thereof at preferably 0.05-2wt./vol.%, especially 0.1-1wt./vol.% concentration to a sustained release suspension pharmaceutical prepared by suspending (A) the first ionic medicine such as codeine, dihydrocodeine, dextromethorphan, phenylpropanolamine, methylephedrine or hydrocodone on (B) an ion exchange resin, then coating the resultant complex A-B with an insoluble polymer, supporting (C) the second ionic medicine having charge of the same kind as that of the ingredient (A), e.g. pheniramine on the same ion exchange resin as the ingredient (B), suspending the prepared C-B complex particles in an aqueous medium and regulating the pH of the suspension pharmaceutical to preferably 3-7. Thereby, the early chemical equilibrium is reached among both the medicines (A) and (C) and the ion exchange resin (B).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a sustained-release aqueous suspension preparation having a stable release property.

[0002]

2. Description of the Related Art Conventionally, a number of sustained-release techniques have been developed in order to enhance the effectiveness and safety of drugs, but these have mainly been related to solid preparations. The liquid is
Since it does not go through the process of drug disintegration / dissolution, there are few individual differences in absorption, immediate effect can be expected, and it is a drug form that is generally preferred because it is easy to take even for children and the elderly. Sustained-release technology is considered to be difficult, and few are currently in practical use.

Among those which have been put into practical use, the invention disclosed in Japanese Patent Publication No. 60-9697 (the title of the invention: formulation) of Ragnarsand et al. Discloses (drug)-(ion exchange resin) composite particles. It is possible to prevent the coating destruction due to the swelling of the ion exchange resin in water by treating it with a solvating agent prior to coating it with an insoluble polymer such as ethyl cellulose (hereinafter sometimes referred to simply as coating). It is a feature. This invention is an excellent invention that enables sustained release of a drug having a short biological half-life in an aqueous medium.

However, in this method, in the preparation containing a second ionic drug such as chlorpheniramine which should maintain immediate release in addition to the drug to be sustained-released, the characteristics of each drug are There is a limit that it is not possible to realize the release property according to the above. That is, when the second ionic drug that should maintain immediate release is added as it is to the aqueous suspension containing the coated (first drug)-(ion exchange resin) complex, The second drug diffuses and penetrates into the (drug)-(ion exchange resin) complex that is gradually coated through the film of the insoluble polymer, and the adsorption equilibrium between the two drugs and the ion exchange resin. The phenomenon of exchanging with the first drug occurs until is achieved. As a result, a part of the first drug is present in the liquid in a free state, while a part of the second drug is present by being adsorbed on the exchange resin, which is preferable for each drug. Releasability will be impaired.

The above-mentioned limitation of the invention of lagner sun is due to the invention disclosed in Japanese Patent Laid-Open No. 60-67418 (title of the invention: liquid long-term release pharmaceutical composition containing ionic drug) of Shoemaker. Significantly improved.

That is, a second drug which should maintain immediate release is pre-adsorbed on an ion-exchange resin in a sufficient amount, but not in excess, and then coated with a first drug which is to be sustainedly released. By coexisting with the (drug)-(ion exchange resin) complex in an aqueous medium, transfer of both drugs to a coated or uncoated ion exchange resin is significantly suppressed,
It was possible to maintain the desired release range for each of the products over a long period of time after production.

However, it has been found that such improved formulations also have significant problems, especially in terms of quality control. That is, in the formulation of shoemaker,
In order to suppress the transfer to the coated or uncoated ion exchange resin, the optimum amount of ion exchange resin to adsorb each drug must be selected, but no matter how the optimum amount can be found, It is difficult to completely prevent the transfer of the drug between the exchange resins, and the transfer gradually progresses. Such drug transfer includes desorption of the drug from the ion-exchange resin, diffusion of the drug in an aqueous medium, re-adsorption of other fractions to the ion-exchange resin, and the drug in the insoluble polymer film. The transfer of such drugs involves suspending the (drug)-(ion exchange resin) complex and the coated (drug)-(ion exchange resin) complex in an aqueous dispersion medium because of the slow diffusion process of It does not end immediately after the production of the desired suspension preparation, but it takes several years to complete at around room temperature, and the equilibrium state is first achieved. In other words, it is possible that the detectable release of the drug will change over time, and in some cases even years, after the formulation is manufactured.

The time course of release of a drug from a drug product by the above mechanism can be minimized, even if it occurs within the range of release acceptable for a drug. Needless to say, it is preferable in terms of quality, but if the release property changes beyond the allowable range, a very serious problem will occur. That is, if the release of a drug immediately after production is higher than the desired range (standard) for it, and then the release decreases due to the aforementioned drug migration and falls within the range of the standard, the product is in the range of the standard. You cannot put it on the market until you enter. Immediately after production, it is within the standard range,
If the product deviates from the standard due to subsequent changes over time, it is necessary to strictly estimate the effective period and take measures such as recovering the product that exceeds the effective period from the market. In order to avoid the above-mentioned inconvenience, there has been a long-felt demand for a technique for realizing a state in which the drug release in the product immediately after production is already close to an equilibrium state.

[0009]

DISCLOSURE OF THE INVENTION Objects and Structures of the Invention The inventors of the present invention have conducted extensive studies for the purpose of improving the above-mentioned inconvenience, and as a result, ionic drugs coexisting in a suspension preparation and coated or uncoated ion exchange. Addition of zwitterionic substances with slightly different interactions to the resin, namely amino acids, to the above suspension formulations results in the formation between these ionic drugs and the coated or uncoated ion exchange resins. It was found that the chemical equilibrium is promoted, and a sustained-release suspension formulation showing stable release of the drug in the system can be obtained immediately after the production for a long period of time, and the present invention has been completed.

That is, in the present invention, the (ionic first drug)-(ion exchange resin) complex coated with an insoluble polymer and the same ion exchange resin as the ion exchange resin are charged with the same charge as the first drug. A sustained-release suspension formulation in which an (ionic second drug)-(ion exchange resin) complex carrying a second drug is suspended in an aqueous medium, and is an early stage between both drugs and the ion exchange resin. The present invention provides a preparation characterized in that an amino acid is added to achieve the chemical equilibrium.

In the present invention, the term "(drug)-(ion exchange resin) complex or complex particles" means a wide range of ion exchange resin particles carrying an active ingredient and is coated (drug)- The (ion exchange resin) complex or the complex particles are those obtained by subjecting the (drug)-(ion exchange resin) complex particles to a polyethylene glycol treatment and then applying a diffusion-inhibiting film of an insoluble polymer such as ethyl cellulose. Refers to. For the sake of convenience, the sustained-release drug coated with an insoluble polymer is called the first drug, and the immediate-release drug not coated is called the second drug. The term "chemical equilibrium between the drug and the ion exchange resin" as used herein means that the transfer of the drug between the ion exchange resins is stabilized and the amount of the drug adsorbed on the ion exchange resin does not change apparently. Say that.

Coated (drug)-(ion exchange resin)
The drug in the complex particles is a drug to be sustained-released, that is, an ionic drug having a relatively short biological half-life, such as codeine, dihydrocodeine, dextromethorphan, phenylpropanolamine, methylephedrine, and hydrocodone. Can be mentioned. Also, uncoated (drug)
The drug in the-(ion exchange resin) complex particles is a drug for which immediate release is to be maintained, that is, an ionic drug having a relatively long biological half-life, and examples thereof include chlorpheniramine.

The average particle size of these (drug)-(ion exchange resin) composite particles in a dry state is preferably in the range of 1 to 500 μm, and most preferably 40 to 110 μm when not coated. In case of 100
It is 250μ. The total content is 3w / v% or less of the whole suspension preparation, uncoated (drug)-
For the (ion exchange resin) composite particles, 1/5 or less of the coated (drug)-(ion exchange resin) composite particles are desirable.

Amino acids for accelerating the chemical equilibrium formed between the drug and the coated or uncoated ion exchange resin include acidic amino acids such as aspartic acid and glutamic acid, glycine, alanine, and cysteine. And basic amino acids such as lysine, arginine, and histidine and salts thereof. According to the present invention, in the system containing no amino acid, the release of the drug (for example, chlorpheniramine) in the uncoated (drug)-(ion exchange resin) complex particles immediately after the production is carried out in a desired range. Until the desired release is achieved (usually about 2 months at room temperature)
While it is necessary to wait for shipment, the system containing the above amino acid shows a release property within a desirable range that can be accepted immediately after the production, and the release ratio with time is increased due to the high rate of reaching the chemical equilibrium value. Shows a relatively stable release rate. On the other hand, the above-mentioned amino acid has almost no effect on the releasability of the drug (eg codeine) in the coated (drug)-(ion exchange resin) complex particles, and the preferable releasability is maintained.

The above-mentioned effect is that the amino acid concentration is 0.05 w / v.
% Or more, the added concentration of the above amino acid is 0.05-
2w / v% is desirable. Most preferably 0.1 to 1 w / v%
And, it exerts its effect more than enough. If the concentration is too high, the amino acid itself in the suspension formulation is not preferable because it affects the interaction between the ion exchange resin and its bound drug as a zwitterionic compound.

In the production process of a suspension preparation, in order to stabilize the dispersion system, a suspending agent such as tragacanth gum and xanthan gum, a specific gravity adjusting agent such as sorbitol and syrup, a preservative, a stabilizer and a pH adjusting agent. Agents, flavoring agents and the like can be used. The release stabilization according to the present invention can be applied to a suspension formulation having a pH of 3 to 7 and having a weakly acidic to neutral region.
Hereinafter, the production method of the suspension preparation according to the present invention will be described with reference to Examples, but the present invention is not limited to these Examples.

Example 1 Production and Evaluation of Suspension Formulation (1) Preparation of Coated (Codeine)-(Ion Exchange Resin) Composite Particles By following the procedure described below, polyethylene glycol was used as a solvating agent, and ethyl cellulose was added. Coated (codeine)-(ion exchange resin) with a coverage of about 11% as a diffusion inhibiting coating
Obtain composite particles. A. (Codeine) - (ion exchange resin) prepared codeine phosphate 95.0g of complex was dissolved in deionized water 950 ml, Amberlite ^R IRP-69 35 While stirring
Add 9.9 g and stir for 1 hour. The obtained ion-exchange resin complex is thoroughly washed on a Buchner funnel, and then dried at a suction temperature of 60 ° C. for 1 hour using a fluidized bed drier to obtain a (codeine)-(ion-exchange resin) complex. B. Preparation of polyethylene glycol-treated resin composite (codeine)-(ion exchange resin) 350 g of the composite,
Polyethylene glycol 40 in 104.8 ml of deionized water
82.5 g of polyethylene glycol aqueous solution was gradually added while mixing, and after kneading for 15 minutes, it was dried at a suction temperature of 40 ° C. for 1 hour using a fluidized bed dryer and treated with polyethylene glycol (codeine)-( Ion exchange resin) complex is prepared. C. Preparation ethylcellulose coating solution 45.0g and Dakekusu ^R 500
Prepared by dissolving 21.2 g of (Durkex) in 130.4 g of acetone and 1304.0 g of methylene chloride. D. Preparation of Coated Resin Complex Using a Wurster type coating device, 400 g of polyethylene glycol-treated (codeine)-(ion exchange resin) complex was coated with a polyethylene glycol-treated resin complex under an intake temperature of 40 ° C. In contrast, 11.0w /
The coating solution is sprayed continuously at a rate of 8 g / min to give a v% (total amount 998) g.

(2) Preparation of chlorpheniramine-resin composite particles 86.0 g of chlorpheniramine maleate and 1 part of deionized water
Dissolve in 634.0 ml and amber light ^R with stirring
200.0 g of IRP-69 is added and stirred for 30 minutes. The obtained ion exchange resin complex is thoroughly washed on a Buchner funnel, and then dried for 1 hour at an inlet temperature of 60 ° C. using a fluidized bed dryer to obtain a (chlorpheniramine)-(ion exchange resin) complex. ..

(3) Preparation of Aqueous Suspension Formulation A natural gum such as tragacanth gum or xanthan gum is dispersed in a polyhydric alcohol such as propylene glycol, and a preservative such as paraben is added if necessary to prepare a slurry. The slurry is then gradually added to an aqueous solution of syrup, sugars and amino acids, namely acidic amino acids such as glutamic acid, neutral amino acids such as glycine and alanine, basic amino acids such as lysine, or salts thereof. Add and stir well to disperse uniformly. Then, the coated (codeine)-(ion exchange resin) composite particles and the (chlorpheniramine)-(ion exchange resin) composite particles which were previously hydrated in a small amount of deionized water containing a surfactant were prepared. The mixture is added and the concentration is adjusted with an appropriate amount of water to prepare suspension formulations shown in Tables 1 and 2 (the formulation is adjusted to pH 3.7 with citric acid).

[0020]

(Table 1) (w / v%) Formulation Rp-1 Rp-2 Rp-3 Rp-4 Rp-5 Coated codeine-resin complex 1.57 1.57 1.57 1.57 1.57 Chlorpheniramine-resin complex 0.18 0.18 0.18 0.18 0.18 Glycine − 0.1 − − − Alanine − − 0.1 − − Glutamic acid − − − 0.1 − Lysine hydrochloride − − − − 0.125 Tragant gum 0.675 0.675 0.675 0.675 0.675 Xanthan gum 0.18 0.18 0.18 0.18 0.18 Propylene glycol 1.0 1.0 1.0 1.0 1.0 Methylparaben 0.15 0.15 0.15 0.15 0.15 Propyl Paraben 0.03 0.03 0.03 0.03 0.03 Corn syrup 30 30 30 30 30 Citric acid 0.1 0.1 0.15 0.1 0.15 Purified water Suitable quantity Suitable quantity Suitable quantity Suitable quantity Total 100 100 100 100 100

[0021]

[Table 2] (w / v%) Formulation Rp-6 Rp-7 Rp-8 Rp-9 Coatedine- resin complex 1.57 1.57 1.57 1.57 Chlorpheniramine-resin complex 0.18 0.18 0.18 0.18 Glycine 0.05 0.5 1.0 2.0 Tragant gum 0.675 0.675 0.675 0.675 Xanthan gum 0.18 0.18 0.18 0.18 Propylene glycol 1.0 1.0 1.0 1.0 Methylparaben 0.15 0.15 0.15 0.15 Propylparaben 0.03 0.03 0.03 0.03 Corn syrup 30 30 30 30 Citric acid 0.1 0.1 0.1 0.1 Purified water Suitable quantity Suitable quantity Suitable quantity Total 100 100 100 100

(4) Evaluation JPX was used for the sustained-release suspension preparations of the above-mentioned 9 formulations immediately after production.
II. Dissolution test of general test method Second method: The release characteristics of codeine and chlorpheniramine were examined by the paddle method. The results are shown in Table 3. Test method Test solution: 500 ml together with input sample Codeine ... 0.1N hydrochloric acid test solution Chlorpheniramine ... 0.4M potassium chloride test solution Rotation speed: 100 rpm Temperature: 37 ° C. Quantitative: HPLC method Rp-1 and Rp- 1 was stored under heating (50 ° C.), and the release characteristics of codeine and chlorpheniramine were evaluated over time. The results are shown in FIGS. 1 and 2. Also, R
With respect to the glycine-containing preparations of p-2 and Rp-6 to Rp-9, the release characteristics of chlorpheniramine at 0.5 hours were shown, and the results of evaluating the concentration dependence of this effect are shown in FIG.

Although the release properties of codeine in the coated (codeine)-(ion exchange resin) complex tend to increase slightly with the passage of time, the rate of reaching the equilibrium value is high immediately after the preparation and the suspension formulation is high. With or without amino acids in
It showed desirable release characteristics. On the other hand, the release property of chlorpheniramine in the (chlorpheniramine)-(ion exchange resin) complex is significantly decreased due to the change with time. Has a low rate of reaching the equilibrium value and could not obtain the desired release characteristics. On the other hand, when the amino acid was contained in the suspension formulation, the release profile was closer to the equilibrium value than immediately after the production, and the stable release profile was obtained within an acceptable range over a long period of time immediately after the production.

Thus, the addition of amino acid is effective in promoting the chemical equilibrium formed between the ionic drug coexisting in the sustained-release suspension preparation and the ion-exchange resin coated or uncoated. It became clear. Similarly, in the sustained-release preparations containing amino acids such as alanine, glutamic acid, and lysine hydrochloride of Examples Rp-3 to Rp-5, the release characteristics of chlorpheniramine are similar to the equilibrium value immediately after the production. And a stable release profile was obtained within an acceptable range over a long period of time.
Further, the effect of accelerating the reaching of this equilibrium value by the amino acid was confirmed to be effective from 0.05% or more in the case of glycine.

[0025]

[Table 3] Release characteristics 0.5 hours immediately after production Prescription codeine Chlorpheniramine Dissolution rate Reach rate Dissolution rate Reach rate Rp-1 29.4 (%) 94.4 (%) 70.8 (%) 69.2 (%) Rp-2 29.8 94.8 56.3 83.7 Rp-3 33.0 98.0 60.3 79.7 Rp-4 34.4 99.4 60.0 80.0 Rp-5 34.7 99.7 60.6 79.4 Arrival rate: 100- (Equilibrium value-Elution rate)% Equilibrium value: Codeine 35.0% Chlorpheniramine 40. 0%

[Brief description of drawings]

FIG. 1 is a graph showing the release characteristics of codeine measured over time.

FIG. 2 is a graph showing the release characteristics of chlorpheniramine measured over time.

FIG. 3 is a graph showing the glycine concentration dependence of the release characteristics of chlorpheniramine at 0.5 hours.

Claims (6)

[Claims] 1. A (ionic first drug)-(ion exchange resin) complex coated with an insoluble polymer and a second ion exchange resin having the same charge as that of the first drug in the same ion exchange resin as the ion exchange resin. Drug loaded (ionic second drug)-
(Ion exchange resin) A sustained-release suspension formulation in which a complex is suspended in an aqueous medium, characterized in that an amino acid is added to achieve an early chemical equilibrium between both drugs and the ion exchange resin. Formulation. 2. The sustained-release suspension preparation according to claim 1, wherein the ionic first drug is selected from codeine, dihydrocodeine, dextromethorphan, phenylpropanolamine, methylephedrine and hydrocodone. 3. The sustained-release suspension preparation according to claim 1, wherein the ionic second drug is chlorpheniramine. 4. The amino acid is glutamic acid, glycine,
The sustained-release suspension preparation according to claim 1, which is selected from amino acids selected from alanine, lysine, and histidine and salts thereof. 5. The sustained-release suspension preparation according to claim 1, wherein the amino acid concentration is 0.05 to 2 w / v%. 6. The sustained-release suspension preparation according to claim 1, wherein the pH of the suspension preparation is in the weakly acidic to neutral range of 3 to 7.