JPH075457B2 - Pharmaceutical composition allowing the release of the active ingredient in a controlled manner - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel compositions, the production of such compositions, and their use in the medical, veterinary and other fields, which allow for the continuous release of the active ingredient in a controlled manner. Regarding

U.S. Pat. Nos. 3,845,770 and 3,916,899 relate to compositions or devices consisting of an active ingredient and a semipermeable membrane which surrounds the active ingredient and provides a passageway. In use, the composition is brought into contact with a fluid which permeates or diffuses through the membrane and dissolves the active ingredient. In this way, an effective osmotic pressure gradient is established across the membrane in which a solution of the active ingredient is drained or released into the surrounding fluid through the passage. U.S. Patent No. 4,
Nos. 160,452 and 4,200,098 relate to similar compositions in which passages or ports are also used to drain the solution. All of these compositions or devices are subject to the disadvantage that passages or ports must be created prior to use of the composition, for example by drilling.

U.S. Pat. No. 4,016,880 relates to compositions or formulations in which the semipermeable membrane or semipermeable wall is provided with structurally weak spots. As a result of the osmotic pressure gradient formed during use, the membrane ruptures at weak points, thereby forming channels at those points, through which the solution drains. The disadvantage of this composition is that the drainage of the solution cannot be easily controlled.

J.Pharm.Sci, 1983, 72 /7,p.772-775 relates tablets had it occurred coated polyvinyl chloride particulate water-soluble pore-forming substance therein is dispersed. In use, the aqueous liquid dissolves the particulate water-soluble pore-forming material to form a highly porous membrane in situ. The aqueous liquid then reaches the tablets within the membrane through the pores thus formed and dissolves them, and the resulting solution is discharged through the pores and out of the membrane.
The disadvantage of this composition is also that the drainage of the solution cannot be easily adjusted.

One of the objects of the present invention is to provide a composition which allows a continuous discharge of a solution of the active ingredient in a controlled manner.

It also provides a composition that can be easily and reproducibly manufactured without the need for any subsequent manufacturing steps, such as drilling, required for many of the aforementioned prior art compositions. Is also an object of the present invention.

Accordingly, the present invention comprises a formulation containing a water-soluble active ingredient, a semipermeable membrane encapsulating the formulation, and a particulate water-soluble pore-forming material dispersed in the membrane, whereby When used in an aqueous environment, the pore-forming material is dissolved to create pores in the semipermeable membrane and the active ingredient is dissolved in the solution, thus penetrating across the membrane between the solution and the aqueous environment. A pressure gradient is created, whereby water from the aqueous environment diffuses through the semipermeable membrane and contacts the active ingredient, while at the same time the active ingredient solution is discharged through the pores of the semipermeable membrane into the aqueous environment. Provide a composition for use in the environment.

Examples of formulations containing water-soluble active ingredients include compressed forms of the active ingredients, optionally mixed with one or more excipients, and coatings of water-permeable polymers as defined below. A prill seed having an active ingredient dispersed in the latter seed and / or coating. In the former case, the compressed form is
Tablets or pills are preferred, and preferred examples of excipients include penetration enhancers and standard formulation excipients such as fillers and binders. Such tablet or pill dosage forms are prepared according to standard techniques well known in the art of pharmaceutics.

As used herein, the prill seed used as the polymer-coated prill seed is a solid particle having a maximum dimension of 0.1-4.0 mm, typically 0.2.
~ 0.3 mm. Prill seeds are usually substantially spherical in shape, but may be oval or even irregular in shape and are commonly used in capsule dosage forms. Preferred examples of prill seeds include those made from sugars such as sucrose and mannitol, starch, salts such as sodium chloride, and waxes. If the active ingredient has a high water solubility, the prill seed may have a low water solubility or even water insolubility. On the other hand, if the active ingredient has low water solubility, it is desirable that the prill seeds have high water solubility so as to increase the osmolality within the composition during its use in an aqueous environment. The preparation of such prill seeds can be carried out according to standard techniques known in the pharmaceutical arts. Alternatively, a wide variety of prill seeds are available on the market. For example, Ingredient Technol
Available from ogy Corporation, Pennsauken, New Jersey, USA.

The water-permeable polymeric coating used for the polymer-coated prill seeds described above is the same polymeric material described below in connection with semipermeable membranes, but with a relatively high permeability to water. A polymer having properties is desirable. Examples of the latter substance include cellulose acetate. It is also desirable that the active ingredient be dispersed within the polymeric material rather than within the prill seed. In such cases, 0.
5 to 5.0 parts by weight are normally used for each part of polymer.

Polymer coated prill seeds can be prepared by standard techniques known in the pharmaceutical arts. For example, prill seed may be coated with a solution of the polymer optionally containing the active ingredient (also in liquid form, or otherwise in suspension). Such coating is usually done in a fluid bed coater, in which the prill seed is coated by spraying in a stream of air in which the coating solution is suspended.

Compositions in which the formulation is a polymer-coated prill seed have many advantages over corresponding compositions in which the formulation is in a compressed form, such as tablets or pills, as described herein. ing. For example, a given dose of the former composition has a larger surface area than the same dose of the latter composition, and thus it is of benefit with respect to the active ingredient that it has low water solubility. That is, the greater the surface area of the composition, the more active ingredient can be dissolved at a higher rate.

Examples of water-soluble active ingredients used in the compositions of the present invention include water-soluble active ingredients used in the fields of human and veterinary medicine and agriculture, such as nutrients, insecticides, fungicides, Includes herbicides, algaecides, vitamins, fertilizers, and soil trace minerals or elements. Specific examples of such active ingredients include d-pseudo efedrin hydrochloride,
Bipropion hydrochloride, soluble potassium salts (for example,
Potassium chloride, potassium citrate, potassium gluconate), chlorophenylene maleate, propranolol hydrochloride, cimetidine, phenylpropanolamine hydrochloride, dextromethorphan bromoate, ascorbic acid, aspirin, acetaminophen, codeine salts , Metmeal, copper sulfate and ammonium nitrate.

As used herein, a penetration enhancer is a substance that has a high molar water solubility, and when the composition of the present invention is used in an aqueous environment, it has a It is a substance that can increase the osmotic pressure. Examples of penetration enhancers include sugars such as sucrose, lactose, fructose and mannitol, and salts such as sodium chloride, potassium chloride and sodium carbonate.

As used herein, a semipermeable membrane is a membrane that is permeable to water but impermeable to the active ingredient or possible penetration enhancers. The film must not be harmful to the active ingredient and must be suitable for the application for which the composition is to be used. The thickness of the membrane is generally 10 to 500 μm, preferably 25 to 50 μm. The membrane is
It may be made of any material suitable for use in the reverse osmosis method or utilized for dialysis. Common examples of such materials include cellulose esters including mono-, di-, tri-acylated and mixed esters, cellulose esters such as ethyl cellulose, nylons, polycarbonates, polydialkyl siloxanes, polymethacrylates, polyesters. Acrylic esters, polyphenylene oxide, polyvinyl alcohol, aromatic nitrogen-containing polymers, polyepoxides and regenerated cellulose are included. Specific examples include cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate, cellulose tripropionate, ethyl cellulose and nylon 6.

The semipermeable membrane is one or more additives, such as plasticizers,
And a water permeability modifier may optionally be included. The plasticizer is preferably a non-migrating plasticizer, and common examples thereof include esters such as phthalic acid, phosphoric acid, citric acid, adipic acid,
Esters such as tartaric acid, sebacic acid, succinic acid, glycolic acid, glyceric acid, benzoic acid and myristic acid,
And sulfonamides. Specific examples include dimethyl phthalate, dipropyl phthalate, di (2-ethylhexyl) phthalate, tributyl phosphate, triacetyl phosphate, and tributyl citrate.

As used herein, a water permeability modifier is a substance capable of enhancing water permeability through a semipermeable membrane. Common examples of such materials include polyalkylene glycols, esters and polyesters of polyalkylene glycols, polyhydric alcohols and esters and polyesters of polyhydric alcohols. A special example is
Polyethylene glycol 300, 400, 600, 1500 and 154
0, polypropylene glycol, 1,3-butylene glycol, glycerin, ethylene glycol dipropionate and ethylene glycol butyrate.

The particulate water-soluble pore-forming material used in the composition of the present invention preferably has a maximum particle size of no more than 500 μm in its longest dimension and an average particle size of 5-100 μm. This material is preferably insoluble in the organic solvent in which the polymeric material is dissolved to form the semipermeable membrane as described herein. Examples of water-soluble pore-forming substances are water-soluble sugars such as lactose, sucrose, sorbitol and mannitol, and sodium carbonate,
Included are salts such as sodium chloride, calcium chloride, potassium chloride and sodium sulfate.

The present invention also provides a method of making a composition, as defined herein, which comprises a solution of a semi-permeable membrane-forming material encapsulating the formulation and a particulate water-soluble pore-forming material. It consists of coating the formulation containing the water-soluble active ingredient with a coating solution containing the suspension for dispersion in the membrane in an organic solvent, and drying the coated formulation.

The coating operation can be carried out, for example, by spraying the formulation with paint in a rotating coating pan or fluid bed coater. The drying operation is performed according to conventional methods.

As described above, it is desirable that the particulate water-soluble pore-forming substance is insoluble in the organic solvent. If this is not the case, the substance can be suspended in an insoluble solvent to obtain a suspension of the substance, then the formulation is coated with the solution and the suspension separately but simultaneously.

Examples of organic solvents include acetone.

As mentioned above, the compositions of the present invention can be used in many areas of human and veterinary medicine. In fact it can be used in any field where a controlled release of the water-soluble active ingredient from the composition is required. It is therefore believed that this composition can be used in the agricultural field, for example for the controlled release of water-soluble fertilizers, soil trace minerals or trace elements, fungicides or herbicides.
However, the primary use of this composition is in human and veterinary medicine.

If the composition of the invention is intended for use in human and / or veterinary medicine, the composition and its components should desirably be pharmaceutically acceptable. Oral pharmaceutical compositions are particularly desirable when the formulation used in the composition is a water soluble polymer coated prill seed as defined herein. Therefore, the most desirable pharmaceutical composition is a capsule containing a prill seed composition.

The present invention will be further explained below with reference to the drawings and examples, but they should not be construed as limiting the present invention in any way.

The drawings are not drawn to scale. FIG. 1 is a plan view of a composition of the present invention, in which the formulation is a polymer coated prill seed.

FIG. 2 is a cross-sectional view taken along the line X--X in the horizontal direction, illustrating the structure of the composition prior to use in an aqueous environment.

FIG. 3 is the same sectional view as that depicted in FIG.
2 shows the structure of the composition after the pore-forming material has dissolved.

Referring to the drawings, there is a prill seed 14 coated with a polymer containing a water-soluble active ingredient, a polymer coating 16 containing a water-soluble active ingredient (Figs. 1, 2 and 3), a semipermeable membrane. 11 and granular water-soluble porous material dispersed in the membrane 11
A composition consisting of 12 and 13 is shown. In most places, the pore-forming substances 12 form clusters across the thickness of the membrane 11, whereas in a few places the substances 13 do not.

When using Composition 10 in an aqueous environment (not shown), the membrane
The pore-forming substances 12 clustered across the thickness of 11 are dissolved in water from the aqueous environment, thereby forming pores in the membrane 11.
15 are formed. Some of the water-soluble active ingredients (Figs. 1, 2 and 3) in the polymer coating immediately adjacent to the pores 15 are contacted with water and dissolved in the solution, whereby the aqueous solution of the active ingredient and the aqueous environment Establish an osmotic pressure gradient across the membrane 11 between and. The effect of the osmotic gradient thus created is that water diffuses or permeates from the aqueous environment through the membrane 11 and contacts the active ingredient, while an aqueous solution of the active ingredient passes through the pores 15 of the membrane 11 into the aqueous environment. Drained, and this process causes the concentration of the active ingredient solution in the membrane 11 to be substantially equal to the concentration of the solution outside the membrane 11 in the aqueous environment, at which point there will no longer be any osmotic pressure gradient between the two fluids. It is absent and continues until most of the active ingredient has been excreted from composition 10 as an aqueous solution into the aqueous environment.

Reference Example 1 Tablets containing 100 mg biupropion hydrochloride and 500 mg lactose were prepared using a conventional tablet press. Fifty tablets were placed in a small pan coater. Cellulose acetate (CA 383-40, Eastman Chemical Product, Inc., King
sport, Tenn.) and polyethylene glycol (Polyglyco)
l E-400, manufactured by Dow Chemical Co., Midland, Mich.) was dissolved in acetone, and then fine powder of lactose (particle size: 2 to 20) was dissolved.
μm) to contain cellulose acetate: polyethylene glycol: lactose in a weight ratio of 40:40:20 and a total solid content.
A polymer solution was prepared by making a 50 g / L mixture. The polymer solution was sprayed onto the tablets in a pan coater to produce coated tablets with a dry coating weight of 27 mg each.

The drug release rate of the tablet composition was determined by allowing the composition to stand in simulated gastric buffer (pH 1.5) at 37 ° C. and periodically measuring biupropion hydrochloride concentration in the buffer. . About 45% biupropion hydrochloride was released after 2 hours, about 70% after 4 hours, and about 90% after 6 hours.

Reference Example 2 Tablets containing 100 mg of biupropion hydrochloride and 500 mg of lactose were prepared using a conventional tablet press. Fifty tablets were placed in a small pan coater. Cellulose acetate (CA 383-40) and polyethylene glycol (Pol
yglycol E-400) in acetone and finely powdered lactose was added to make a mixture containing cellulose acetate: polyethylene glycol: lactose in a weight ratio of 60:13:20 and a total solid content of 50 g / L. A coalescing solution was prepared. The polymer solution was sprayed onto the tablets in a pan coater to produce coated tablets with a dry coating weight of 35 mg each.

The drug release rate of the tablet composition was determined by allowing the composition to stand in simulated gastric buffer (pH 1.5) at 37 ° C. and periodically measuring biupropion hydrochloride concentration in the buffer.
After about 2 hours, about 10% biupropion hydrochloride was released,
About 25% was released after 4 hours, about 40% after 6 hours, and about 55% after 8 hours.

Reference Example 3 A tablet containing 120 mg of d-pseudoehuedrin hydrochloride, 5 mg of triprolidine hydrochloride, 125 mg of lactose and 28 mg of starch was prepared using a conventional tablet press. Fifty tablets were placed in a small pan coater. Cellulose acetate (CA398-10, Eastman Chemical Products, Inc., Kingsp
ort, Tenn.) and polyethylene glycol (Polyglycol)
E-400) is dissolved in acetone, and powdery sodium carbonate (particle size: 30 to 200 μm) is added to the mixture, and a weight ratio of cellulose acetate: polyethylene glycol: sodium carbonate is 4: 40: 2.
Polymer solutions were prepared by making a mixture containing 0 and a total solids content of 50 g / L. The polymer solution was sprayed onto the tablets in a pan coater to produce coated tablets with a dry coating weight of 64 mg each.

The drug release rate of the tablet composition was determined by allowing the composition to stand in simulated gastric buffer (pH 1.5) at 37 ° C and measuring drug concentration periodically. After 1 hour, about 33% of d-pseudoehuedrin hydrochloride and 32% of triprolidine were released, after 2 hours, about 53% of each drug was released, and after 3 hours, about 71% and 74% of husband and wife, After 4 hours, about 97% and 85% of the drug was released, respectively.

Example 1 Sucrose / starch prill seed (Nu-Pareil 20/25 mesh prill, Ingredient Technology Corp., Pennsauke
A total of 40 g of N, NJ) was placed in a cylindrical bed (16 inches long x 1.5 inches diameter) and fluidized with 30 psi dry compressed air. Next, prill 12 g of cellulose acetate (CA398
−10, Eastman Chemical Products, Inc., Kingsport, Ten
n.) and d-pseudoephredrine hydrochloride (36 g) in ethanol (200 ml) and dichloromethane (400 ml) using a 30 psi airbrush. Partial drying was performed intermittently to prevent agglomeration. The polymer-coated prill was removed from the bed and dried for 2 hours.
The prill was then returned to the fluid bed and 7 g of cellulose acetate (CA
398-10) and 1 g of polyethylene glycol (Polyglycol
E-400, Dow Chemical Co., Midland, Michigan) in a solution of 240 ml of acetone in 2 g of powdered sodium carbonate (particle size: 30
˜200 μm) in suspension. The prill seed composition thus formed was then dried.

To measure the drug release rate of a prill seed composition,
The composition was left at 37 ° C. in various concentrations of sodium chloride solution to alter the osmotic driving force of drug release and the concentration of d-pseudoephedrine hydrochloride was measured periodically. The drug release rate was 90 mg / hr. When the sodium chloride concentration was 0%, and the release rate was 75 mg when the concentration was 5%.
The release rate was 45 mg / hr. at 10 mg / hr. and 10%, and the release rate was 10 mg / hr. at 20%.

Example 2 Sucrose seed prill (Nu-Pareil) was coated essentially with the procedure of Example 4 with an aspirin (75%)-CA-398-10 (25%) mixture, but only ethanol-.
Acetone was used instead of dichloromethane (total solids content is 10% by weight). The polymer-coated prill seeds are dried before being added to cellulose acetate (CA-398-40, Eastm).
an Chemical Products, Inc., Kingsport, Tenn.): Poly
glycol E-400: Fine powder lactose (particle size: 5-20 μm)
Acetone solution of 40:40:20 mixture (total solids content 5% by weight)
Recoated by. The prill seed composition thus formed was then dried.

The drug release rate was measured as in Example 4. After 2 hours, about 60% of aspirin had been released. After 4 hours, about 80% was released, and after 8 hours, about 90% was released.

[Brief description of drawings]

FIG. 1 is a plan view of a composition of the present invention, in which the formulation is a polymer coated prill seed. FIG. 2 is a cross-sectional view taken along the line X--X in the horizontal direction, illustrating the structure of the composition prior to use in an aqueous environment. FIG. 3 is the same sectional view as that depicted in FIG.
2 shows the structure of the composition after the pore-forming material has dissolved.

Front Page Continuation (72) Inventor Kelly Lincoln Smith Bend, Oregon, USA. Dayton Road 19295 (56) Reference JP 58-162518 (JP, A) JP 56-167617 (JP, A) JP 52-106379 (JP, A) JP 57-11912 (JP , A) JP 60-41609 (JP, A) JP 60-174713 (JP, A) JP 60-185711 (JP, A)

Claims (8)

[Claims] 1. A prill seed containing a water-soluble active ingredient and having a coating of a water-permeable polymer, wherein the active ingredient is dispersed in the prill seed and / or the coating. A semipermeable membrane encapsulating the composition, and a particulate water-soluble pore-forming substance dispersed in the membrane so that the pore-forming substance is dissolved when used in an aqueous environment. Making pores in the semipermeable membrane, the active ingredient is dissolved in the solution, thus creating an osmotic pressure gradient across the membrane between the solution and the aqueous environment, allowing water from the aqueous environment to pass through the semipermeable membrane. A composition for use in an aqueous environment, characterized in that it diffuses into contact with the active ingredient and at the same time a solution of the active ingredient is discharged through the pores of the semipermeable membrane into the aqueous environment. 2. The composition according to claim 1, wherein the water-permeable polymer is cellulose acetate. 3. The active ingredient is an active ingredient used in the field of human or veterinary medicine or in the field of agriculture,
The composition according to claim 1 or 2. 4. A semipermeable membrane comprising cellulose ester, cellulose ether, nylon, polycarbonate, polydialkylsiloxane, polymethacrylic acid ester, polyacrylic acid ester, polyphenylene oxide, polyvinyl alcohol, aromatic nitrogen-containing polymer, polyepoxide,
Alternatively, the composition according to any one of claims 1 to 3, which is made of regenerated cellulose. 5. The composition according to any one of claims 1 to 4, wherein the granular water-soluble pore-forming substance is made of a water-soluble sugar or salt. 6. The method according to claim 1, wherein the active ingredient is an active ingredient used in the field of veterinary medicine or human medicine, and all other ingredients are pharmaceutically acceptable. The composition according to any of items 5 to 5. 7. A formulation is in the form of a capsule, which is a prill seed having a coating of water permeable polymer, wherein the active ingredient is dispersed in the prill seed and / or the coating. The composition according to claim 6. 8. A prill seed containing a water-soluble active ingredient and having a coating of a water-permeable polymer, wherein the active ingredient is dispersed in the prill seed and / or the coating. A semipermeable membrane encapsulating the composition, and a particulate water-soluble pore-forming substance dispersed in the membrane so that the pore-forming substance is dissolved when used in an aqueous environment. Making pores in the semipermeable membrane, the active ingredient is dissolved in the solution, thus creating an osmotic pressure gradient across the membrane between the solution and the aqueous environment, allowing water from the aqueous environment to pass through the semipermeable membrane. Production of a composition for use in an aqueous environment, characterized in that it diffuses into contact with the active ingredient and at the same time a solution of the active ingredient is discharged through the semipermeable membrane through the pores into the aqueous environment. A method of forming a semi-permeable membrane-encapsulating solution of a substance, comprising: After coating a formulation containing a water-soluble active ingredient with a paint containing an aqueous solvent, a suspension for dispersing the water-soluble pore-forming substance in a membrane, and drying the coated formulation. The above-mentioned manufacturing method consisting of the following.