JP2002212062A - Controlled release composition - Google Patents

Abstract

(57) [Summary] The object of the present invention is to release most of the contained drug within a short time from the start of drug release and to stay at the release site regardless of the length of the lag time. An object of the present invention is to provide an administration composition capable of maintaining a high local concentration as compared with a preparation. SOLUTION: This pharmaceutical composition comprises a core comprising a drug and a swelling agent, and a coating film layer around the core, wherein (a) the coating film layer is formed of a water-insoluble and water-permeable substance. A portion of the coating film layer is (1) thinner in film thickness than the other coating film layer portions, or (2) accompanying the swelling of the nucleus as compared with the other coating film layer portions. The composition has a weak breaking strength against stretching of the coating film layer, and (a) after being orally administered to a warm-blooded animal,
The present invention provides a pharmaceutical composition characterized in that a part of the coating film layer is cracked by swelling of the swelling agent after a predetermined time, and the drug in the nucleus is released outside the composition.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a delayed-release controlled composition in which a drug is rapidly released after a certain period of time by the action of a swelling agent.

[0002]

BACKGROUND OF THE INVENTION Among the controlled release compositions, the usefulness of a preparation which does not release a drug immediately after administration but releases a drug only after a certain period of time has been already known. The time from the time of administration to the start of drug release is called lag time.By adjusting this lag time, drug release at the highest absorption site and the most suitable for exhibiting drug efficacy in accordance with the circadian rhythm It is possible to release the drug at a certain time.

[0003] Numerous coating techniques have been established as techniques for achieving this lag time. However, common techniques for creating lag time require several hours or more to release the entire amount of drug in the contents. For example, Japanese Patent Application Laid-Open No. Hei 10-81634 describes a time-release preparation by a coating technique using a base that requires a long time to dissolve in the digestive tract, but this is intended for the sustained release of a drug. A composition.
Also, Japanese Patent Application Laid-Open No. Sho 62-30709, Japanese Patent Application No.
No. 2442 discloses time-release preparations in which the swelling agent contained in the nucleus breaks the coating and releases the drug, but these are also compositions for the purpose of sustained release of the drug. U.S. Pat. No. 5,840,332 describes a time release formulation in which the swelling agent contained in the coating layer breaks through the coating and releases the drug, but has a lag time of up to 9 hours as described herein. As the lag time increases, so does the time required for the full release of the drug, and more than 4 hours are required for more than 80% of the drug content to be released. In addition, Chemical Pharmaceutical Bullet
in 1995 No. 43, pp. 311-314, reported a tablet with a lag time due to a gel-forming base. Although the total release time was not delayed due to the extension of the lag time, it was 80% or more of the drug content. It takes 6 hours or more to be released.

As another approach, release devices have been established that control drug release by osmotic pressure.
For example, US Pat. No. 4,587,117 and US Pat. No. 4,693,895 describe osmotic pumps provided with an enteric coating. However, it is necessary to set a lag time for a long time without any drug release from the mechanism. Is difficult and is a composition mainly intended for sustained release of a drug. Gut should be reviewed by humans using the relevant composition
As reported in 1990, 31 pp. 106-110, although lag time is 4 hours, it takes more than 10 hours after the start of release to release 80% of the content.

[0005] Compositions are also known which use a special technique to release most of the contents within a short time after a predetermined lag time. U.S. Pat. No. 5,817,335 describes an osmotic composition comprising two housings. However, in order to generate an osmotic pressure, an advanced technique of closely contacting the two housings without a gap is required, and it is not common because there are a plurality of complicated steps. Similarly, British Patent No. 2 230 442 describes a composition comprising a water-insoluble body and a plug of a water-swellable substance. Absent. British Patent No. 2,245,492 describes a composition having a surface coated with a hydrophobic substance and a surfactant. It is described that the lag time can be set in proportion to the thickness of the coating film, but the mechanism of release is unknown. In the above three methods, after the contents are released, the drug moves to the lower gastrointestinal tract by normal gastrointestinal transit. Thus, local high concentrations of the drug are only temporarily achieved.

[0006] For the purpose of drug release in the small intestine, enteric-coated preparations are generally used. However,
When the release site is located in the middle and lower part of the small intestine, there is an individual difference in the intestinal pH and it is necessary to coat the enteric base thickly, so that the enteric base moves to the large intestine before it is completely dissolved. Possibility of doing so and poor reliability. In addition, since the enteric preparation is not necessarily intended to release the entire amount of the drug in a short time, it is difficult to concentrate the drug at a target site.

[0007]

In the above-mentioned coating method and osmotic pressure method, it takes several hours from the start of the release of the drug to release the entire amount of the contained drug, especially if the lag time becomes long. Indeed, the time required for full release is often extended. Alternatively, the drug is released in the form of a pulse in small portions. These forms are effective for drugs with a wide absorption site or drugs that require long-lasting, but drugs that need to reach an effective blood concentration in a short time, It is not suitable for a desired drug, a drug that exhibits tolerance, a drug that requires a temporarily high blood concentration at a specific time according to the circadian rhythm, and the like. In the case of the drug, it is desired to release the entire amount of the drug immediately after a predetermined time has elapsed.

[0008] In the case of a drug having a limited absorption site, a drug affected by a degrading enzyme specifically present in each site, or a drug absorbed through a transport carrier specifically present in each site, the above-mentioned coating is used. The osmotic method is not suitable because only a part of the contained drug can be used. In the case of such a drug, it is desired to release the entire amount of the contained drug promptly at a predetermined site rather than after a lapse of a predetermined time. In order to achieve this, a composition which releases most of the contents within a short time after a predetermined lag time is effective. In addition to the above-mentioned release forms, the effect of the drug is expected to be increased if the drug can be retained at the release site.

An example of a drug in which the above-mentioned drug release form is desirable is a drug absorbed through a Peyer's patch. Oral vaccine is Vaccine 199
It is described in, for example, pp. 1677-1685, No. 6, 2014. With respect to drug absorption through Peyer's patches, use of a mucoadhesive base is one of the techniques for improving the absorbability. For example, Natu
re 1997, 386, pages 410-414, reports the effect of microspheres comprising a fumaric acid-sebacic acid copolymer as a mucoadhesive base. However, since the dosage form is normal oral administration, the time required for each microsphere to reach the small intestine is not uniform, and the administered microspheres are distributed throughout the intestine and cannot be concentrated in one place. . Therefore, it is not possible to achieve a local high concentration at a specific site in the small intestine.

[0010] In humans, it is known that the distribution of Peyer's patches is abundant in the lower small intestine. In addition, normal small intestinal epithelial cells, which normally do not show uptake effects, are induced, and may exhibit drug uptake effects similar to Peyer's patches.
Science, 1997, 277, pages 949-952, allowing more efficient drug uptake. However,
It is assumed that the epithelial cells are limited to those near Peyer's patches. Summarizing the above, for a drug absorbed through the Peyer's patch, a dosage form capable of releasing the drug at a burst in the lower part of the small intestine, retaining the drug at the release site, and maintaining a local high concentration is desired. . However, a composition for realizing it has not been found so far.

[0011] The problems in the prior art described above,
And in view of the problem, as a result of intensive studies by the present inventors,
Regardless of the length of the lag time, most of the contained drug is released within a short time from the start of drug release, stays at the release site, and can maintain a high local concentration compared to the normal formulation I found something. In one embodiment of the present invention,
In particular, an effective administration composition has been found for drugs absorbed through Peyer's patches.

[0012]

That is, the present invention relates to a pharmaceutical composition comprising a core comprising a drug and a swelling agent, and a coating layer surrounding the core. Is composed of a water-insoluble and water-permeable substance, and a part of the coating film layer is (1) thinner in film thickness than other coating film layer portions, or (2) is formed on another coating film layer portion. In comparison, the composition has a weaker breaking strength against stretching of the coating film layer accompanying the swelling of the nucleus,
And (a) after oral administration to a warm-blooded animal, after a predetermined time, a swelling of the swelling agent causes a crack in a part of the coating film layer, and the drug in the nucleus is released outside the composition. The present invention provides a pharmaceutical composition characterized by being performed.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION In the embodiment of the present invention, a core tablet containing a drug and a swelling agent is coated with a water-insoluble and water-permeable substance. The nucleus can be produced by direct compression, granule compression, or round production in a conventional manner. The core may also contain other additives that can be used as pharmaceutical additives as long as the effect is not impaired, excipients, lubricants, binders, corrigents, plasticizers for coating films, Etc. may be included.

In one embodiment of the present invention, a specific portion of a coating film made of a water-insoluble and water-permeable substance is thin.
In general, a coating having a uniform film thickness is generally applied to pharmaceuticals. In order to obtain the form of the present invention, a method of applying a uniform coating to the composition and then masking a part of the surface to reduce the film thickness at the part, a method of applying the uniform coating to the composition. A method of scraping off a part of the coating after the application, applying a uniform coating to the composition, and then melting and fixing a cap or film having the same composition as the coating film on a part of the surface to reduce the film thickness other than the part. A method of using a composition having projections on the surface to reduce the thickness of the projection by shaving the projections due to friction between the compositions during coating, and a method of using a composition having a depression on the surface to cover the projections. Can be manufactured by a method of reducing the thickness of the film.

The method of applying a uniform coating to the composition and then masking a portion of the surface to reduce the thickness of the portion is performed by using a composition having a core as shown in FIG. 1 (a). Fig. 1
As shown in (b), coating is performed uniformly to an arbitrary thickness. In the second step, as shown in FIG. 1 (c), masking is performed so that a part of the composition surface cannot be further coated,
As shown in FIG. 1 (d), coating is performed again with a uniform thickness.
In this method, the masking is removed after the coating is completed to obtain a composition in which the thickness of the portion is smaller than that of the unmasked portion as shown in FIG. 1 (e). By arbitrarily changing the coating amount before and after masking, it is possible to arbitrarily adjust the difference in film thickness between a thick portion and a thin portion.

The method of shaving off a part of the coating after applying a coating having a uniform thickness to the composition is as follows: a core composition as shown in FIG. 2 (a); and a core composition as shown in FIG. 2 (b). After uniformly coating to an arbitrary thickness as described above, a part of the coating film on the composition surface is shaved to an arbitrary thickness using a laser marker or the like as shown in FIG. It is. A method of applying a uniform coating to the composition and then melting and fixing a cap or film having the same composition as the coating film on a part of the surface to reduce the thickness of the part other than the part is shown in FIG. A core composition as shown in a) is uniformly coated to an arbitrary thickness as shown in FIG. 3 (b), and a cap or film formed separately as shown in FIG. 3 (c) is formed. This is a method of preparing a composition having portions having different film thicknesses as shown in FIG. 3 (d) by fixing the molded product. The substance used as a molded product is not particularly limited as long as it has a film-forming property, but it is preferable that the substance has the same composition as the coating base.

The method of using a composition having projections on the surface to reduce the thickness of the projections by shaving the projections due to friction between the compositions during coating is described in FIG. 4 (a). Is a method in which a composition having protrusions is formed and coated by a pan coating method. The fact that the protrusions on the surface are gradually shaved due to the friction between the compositions during coating and the friction between the composition and the coating pan is used to make use of the fact that the surface of the protrusions is hardly covered with the coating film.
Since the portion without protrusions is coated with the film from the start of coating, the finished composition has a partially reduced thickness of the protrusions as shown in FIG. 4 (c).

The method of reducing the film thickness of the portion by using a composition having a depression on the surface is to prepare a composition having a depression on the surface as shown in FIG. This is a method of coating. Since the coating spray liquid does not easily reach the surface of the recess, the finished coating film is thinner than the portion without the recess as shown in FIG. 5 (c).

The swelling agents used in the present invention include carmellose, carmellose sodium, croscarmellose sodium, carmellose calcium, wheat starch, rice starch, corn starch, potato starch, partially pregelatinized starch, hydroxypropyl starch, carboxy. Examples include, but are not particularly limited to, methyl starch sodium, crospovidone, crystalline cellulose, methyl cellulose, polyacrylic acid and copolymers thereof. Among them, croscarmellose sodium, crospovidone and sodium carboxymethyl starch are preferred.

The water-insoluble and water-permeable substance used in the present invention is not particularly limited as long as it has a film-form performance. Ethyl cellulose, cellulose derivatives such as cellulose acetate, polyacrylic acid and its derivatives and their copolymers, polymethacrylic acid derivatives such as aminoalkyl methacrylate copolymers and their copolymers, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, Wax, shellac and the like. In addition, even if it is not a single substance, water-insoluble and water-permeable properties due to multiple substances such as complex formation of polyacrylic acid and polyethylene glycol, complex formation of polyacrylic acid and polyvinylpyrrolidone, or complex formation of polylysine and alginic acid May be one with. Among these substances, those having low ductility of the formed film are preferable, and ethyl cellulose and cellulose acetate are preferably used.

One embodiment of the present invention is a mode in which the composition of a specific portion of a coating film made of a water-insoluble and water-permeable substance is different. Examples of different compositions include a form in which the plasticizer of the coating film is present only in the relevant portion, a form in which the plasticizer concentration in the relevant portion is higher than in other coated portions, and the like. When a plasticizer is included in the coating film, a decrease in the breaking strength of the film is a generally observed phenomenon. In general, in pharmaceutical products, it is common to apply a coating having a uniform film composition. In order to obtain this embodiment, it is possible to prepare the core by using a core in which the composition of the core is not uniform and a plasticizer of a water-insoluble and water-permeable substance is distributed outside the core. As a specific example, a three-layer tablet in which the central layer is composed of a swelling agent and a plasticizer and the upper and lower parts thereof are composed of a drug and an excipient is prepared, and coated with a water-insoluble and water-permeable substance. It is possible to permeate the coating film and reduce the breaking strength of a portion of the coating film near the central layer. As another example, a similar effect can be obtained by winding a tape containing a plasticizer around a core and coating the core with a water-insoluble and water-permeable substance.

In the present invention, a foaming agent can be included in the nucleus in order to speed up the release after the start of the drug release. For example, tartaric acid, sodium hydrogen carbonate, potato starch, citric anhydride, sodium lauryl sulfate, lauromacrogol, and the like are used.

In the present invention, the drug and the swelling agent are present in the nucleus, but they may be mixed uniformly or separated from each other. A separated state is one in which the core has one component at the center, like a dry-coated tablet, and the other component covers the outside, and the core, like a two- or three-layer tablet, has a vertical core. A state in which the layers are separated into layers in the direction or a state in which the layers are separated concentrically into ring-shaped layers for each component are shown.

As the substance for forming the water permeable control membrane used in the present invention, a water-soluble or hydrogel-forming substance may be used. In the former case, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, polyethylene glycol and the like can be mentioned, and in the latter, carboxyvinyl polymer, polyvinyl alcohol, gelatin and the like can be mentioned.

As the substance for forming the water permeability controlling membrane used in the present invention, an enteric base may be used. Examples include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate,
Carboxymethyl ethyl cellulose, cellulose acetate phthalate, cellulose acetate trimellitate, aminoalkyl methacrylate copolymer, methacrylic acid copolymer and the like are used.

Although the main feature of the present invention is rapid release of the drug, a part or all of the contained drug may be processed for sustained release so that the dissolution after release is delayed. Sustained release processing means matrix processing in which granules and sizing are performed by a conventional method with a base that gradually dissolves or decomposes drugs, excipients, binders, etc., or granulation and sizing in a conventional manner This shows processing in which a base that gradually dissolves or decomposes in a granule containing a drug is coated by a conventional method. By adopting such a form, it is possible to quickly reach the effective blood concentration by primary elution after administration, supplement the subsequent decrease in concentration by secondary elution, and maintain the effective blood concentration.

As the above-mentioned slowly soluble base, a water-soluble base and a water-permeable base can be used. Examples of the water-soluble base and the water-permeable base include hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carmellose sodium, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, and cellulose. Acetate phthalate, cellulose acetate trimellitate, ethyl cellulose, cellulose derivatives such as cellulose acetate, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, gelatin, shellac, polyacrylic acid and its derivatives and their copolymers, polymethacrylic acid and its derivatives and Their copolymers, polyacrylic acid and polyethylene Can be exemplified glycol complex, polyacrylic acid and polyvinylpyrrolidone complex, Complex by polylysine alginate, one or two or more selected from the group consisting of.

A biodegradable base can be used as the base that gradually decomposes. Examples of the biodegradable base include one or more selected from the group consisting of polyglycolic acid, polylactic acid, and lactic acid / glycolic acid copolymer.

In the present invention, the nucleus may further contain a mucoadhesive base for retaining the drug at the release site after the release of the drug. Alternatively, the nucleus may contain a swelling agent having mucoadhesive properties. Examples of the mucoadhesive base include carmellose sodium, croscarmellose sodium,
Hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, methylethylcellulose, polyacrylic acid and its copolymer, polyethylene glycol and its copolymer, chitosan, sodium alginate and the like are used. Preferably, croscarmellose sodium, which is a swelling agent having a mucoadhesive property on the nucleus, is used.

In the embodiment of the present invention, a specific portion of a coating film made of a water-insoluble and water-permeable substance for coating a core tablet containing a drug and a swelling agent is thin, or the specific portion has a different composition. It is a form. The portion is not particularly limited, but preferably has a form in which the cross-sectional area is increased upon generation of a crack in the coating film due to swelling of the swelling agent and subsequent collapse of the core. As an example, when the portion is a linear portion that makes a round or almost a round around the outer periphery of the composition and the composition divides into approximately two, the nucleus is almost divided into two by swelling and the cross-sectional area is wide, so that the drug release is desirably accelerated. . Preferably, 30% or more, preferably 50% or more of the amount of drug contained in the nucleus is released within 1 hour after the start of drug release.

The composition of the present invention obtained as described above is capable of releasing a drug after a certain lag time from administration. The lag time can be set arbitrarily, the composition and ratio of the swelling agent contained in the nucleus, the composition and thickness of the coating film made of a water-insoluble and water-permeable substance, the composition and the film of the water permeability control film. Adjusted by thickness.

The composition of the present invention can also release a drug specifically in the middle and lower part of the small intestine. In humans, individual differences in gastric residence time and dietary variation are large, ranging from minutes to 10 hours. However, the small intestine retention time was almost constant at three to three and a half hours, and there was no influence from meals. Annals New York Academy of Sciences
Reported in 1991, 618, pages 428-440. Therefore, when the drug release is controlled only by the lag time, the release site in the body of the drug is inevitably different due to the difference of the residence time in the stomach, and the drug is released in any of the stomach, small intestine, and large intestine. However, the composition coated with the enteric base according to one embodiment of the present invention reaches the small intestine, and the enteric base is dissolved, and drug release starts after a predetermined time has elapsed. Therefore, if the drug release is set within three and a half hours after reaching the small intestine, the drug can be specifically released in the middle and lower parts of the small intestine with good reproducibility without being affected by the length of the gastric residence time. It is possible. In addition, since the time required from the start of the release of the drug to the release of the entire amount is short, the release of the drug is concentrated at the target site, and the drug can be used efficiently.

Similarly, the composition coated with the enteric base of one embodiment of the present invention can release a drug specifically in the large intestine. In this case, if the drug release of the present composition is set to 3 hours and a half after arrival in the small intestine, the drug is specifically released in the large intestine with good reproducibility without being affected by the length of the gastric residence time. It is possible. In addition, since the time required from the start of the release of the drug to the release of the entire amount is short, the release of the drug is concentrated at the target site, and the drug can be used efficiently.

The composition of the present invention releases a drug specifically in the middle, lower part, or large intestine of the small intestine and then stays at the release site by the action of a mucoadhesive base or a mucoadhesive swelling agent. It is also possible to maintain a locally high concentration state. When the drug is released at the absorption site of the drug, the drug is concentrated at the target site for a long time, and the drug can be used efficiently.

Examples of the drug of the present invention include, but are not limited to, anti-inflammatory steroids, analgesic anti-inflammatory drugs, antitussive expectorants, antihistamines, antiallergic drugs, antirheumatic drugs, bronchodilators, antiemetic drugs, Migraines, sleep-inducing drugs, sleep sedatives, vitamins, sex steroid hormones, antitumor drugs, vasopressors, antithrombotics, anti-anxiety / psychotropic drugs, antiepileptics, anti-ulcer drugs, analgesics, immunity Inhibitors, vaccines, toxoids and peptide and proteinaceous drugs. Specifically, for example, hydrocortisone, prednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, fluticasone, mometasone, fluocortin,
Inflammatory steroids such as budesonide, salbutamol, salmeterol, acetaminophen, phenacetin, aspirin, aminopyrine, sulpyrine, phenylbutazone, mefenamic acid, flufenamic acid, ibfenac,
Analgesic and anti-inflammatory drugs such as ibuprofen, alclofenac, diclofenac, indomethacin, antitussive expectorants such as sodium cromoglycate, codeine phosphate, isoproterenol hydrochloride, antihistamines such as diphenhydramine, triprolidine, isotipendyl, chlorpheniramine, amlexanox , Azelastine, Ozacrel, Tranilast, Ketotifen and other antiallergic drugs,
Anti-rheumatic drugs such as penicillamine, auranofin, budiramine, actarit, methotrexate, bronchodilators such as theophylline, ondansetron, granisetron, antiemetic drugs such as metoclopramide, cisapride, domperidone, etc. Headache drugs, hypnotic-inducing drugs such as brotizolam, sleep sedatives such as barbital, pentobarbital salt, secobarbital salt, vitamins such as cyanocobalamin and mecobalamin, sex steroid hormones such as estradiol, estriol, progesterone, and testosterone; tamoxifen; Antitumor drugs such as tegafur, vasopressors such as epinephrine, antithrombotic drugs such as warfarin, antianxiety / psychotropic drugs such as diazepam and nitrazepam, and antitensile drugs such as phenytoin Medicine, cimetidine, anti-ulcer drugs such as ranitidine, analgesics such as buprenorphine, cyclosporine, azathioprine, mizoribine, methotrexate,
Immunosuppressants such as cyclosporine, tacrolimus hydrate, gusperimus hydrochloride, influenza vaccine, mumps vaccine, varicella vaccine, rubella vaccine, measles vaccine, pertussis vaccine, hepatitis A vaccine, hepatitis B vaccine, rabies vaccine, BCG vaccine, polio Vaccines such as vaccines, cholera vaccines, Japanese encephalitis vaccines, pneumococcal vaccines, and toxoids such as diphtheria toxoid, tetanus toxoid, and gall toxoid. The peptide / proteinaceous drug of the present invention includes luteinizing hormone-releasing hormones, growth hormone-releasing factors, somatostatin derivatives, vasopressins, oxytocins, hirudin derivatives, enkephalins, corticotropin-stimulating hormone derivatives, bradykinin Derivatives,
Calcitonins, insulin, glucagon derivatives, growth hormones, growth hormone-releasing hormones, luteinizing hormones, insulin-like growth factors, calcitonin gene-related peptides, atrial natriuretic peptide derivatives, interferons, erythropoietin, Granulocyte colony formation stimulating factor, macrophage formation stimulating factor, parathyroid hormones, parathyroid hormone releasing hormone, prolactin, thyroid stimulating hormone releasing hormone, angiotensin, prostaglandins and the like.

Of these, a drug that needs to reach an effective blood concentration in a short time, a drug whose blood concentration is desirably reduced immediately after the onset of the drug effect, a drug that develops tolerance, and a circadian rhythm are preferable. In addition, drugs that require a high blood concentration at a specific time, drugs whose absorption sites are limited, drugs that are affected by a degrading enzyme that exists specifically for each site, and transport carriers that specifically exist for each site Drug absorbed through the like.

Particularly, in the case of a drug absorbed through the Peyer's patch, since the distribution of Peyer's patch in humans is large in the lower part of the small intestine, the release of the drug, which is one mode of the present invention, is set within three and a half hours after reaching the small intestine. A composition containing a mucoadhesive base in the nucleus is desirable. More preferably, a composition containing a base agent granulated and sized with a base that gradually decomposes and croscarmellose sodium having characteristics of both a swelling agent and a mucoadhesive base in a core is preferable.

In particular, as a drug absorbed through the Peyer's patch, an anti-inflammatory steroid, a sex steroid hormone, an immunosuppressant, a vaccine, a toxoid and a peptide / protein drug are preferably used.

[0039]

EXAMPLES The present invention will be described below with reference to examples.

Example 1 Microcrystalline cellulose 600 g, croscarmellose sodium 400 g, food color blue No. 1 20
g and 6 g of stearic acid were mixed with a cross rotary mixer, and directly punched to produce a core tablet having a diameter of 7 mm and a weight of 180 mg. Cellulose acetate dissolved in ethyl lactate was sprayed uniformly on 300 g of the tablet, and a coating equivalent to 2.5 or 3% by weight based on the original tablet weight was applied using a pan coater. After drying, the tablets were taken out, and an adhesive tape having a width of 1 mm was attached to the center of the outer periphery of the tablet side face, and subjected to masking. The tablets were put again in a pan coater, sprayed with cellulose acetate under the same conditions, and coated in a total amount of 5% by weight based on the original tablet weight. After drying, the tablets were removed, the masking was removed, and a time-controlled tablet having a thin portion was obtained.

Comparative Example 1 A core tablet was prepared in the same manner as in Example 1. Thereafter, 300 g of the tablet was sprayed with cellulose acetate dissolved in ethyl lactate, and a coating having a uniform film thickness equivalent to 5% by weight based on the original tablet weight was applied using a pan coater.

Example 2 600 g of microcrystalline cellulose, 400 g of sodium carboxymethyl starch, food color blue 1
No. 20g and stearic acid 6g were mixed with a cross rotary mixer, and a core tablet having a diameter of 7mm and a weight of 180mg was produced by direct hitting. Thereafter, coating was carried out under the same conditions as in Example 1 to obtain a time-controlled tablet having a thin portion corresponding to 2.5% by weight on the side surface.

Example 3 600 g of microcrystalline cellulose, 400 g of croscarmellose sodium, propranolol hydrochloride
40 g and 6 g of stearic acid were mixed by a cross rotary mixer, and a core tablet having a diameter of 7 mm and a weight of 180 mg was prepared by direct hitting. Cellulose acetate dissolved in ethyl lactate was sprayed uniformly on 300 g of the tablet, and a coating equivalent to 5% by weight based on the original tablet weight was applied using a pan coater. After drying, take out the tablet and irradiate it with excimer laser.
Approximately 0.1mm
Etching was performed so as to make a round around the outer edge in width.

Comparative Example 2 A core tablet was prepared in the same manner as in Example 3, coated, and stored without being etched by irradiation with an excimer laser.

Example 4 300 g of a time-controlled tablet prepared under the same conditions as in Example 1 was sprayed with cellulose acetate phthalate dissolved in 1: 1 ethyl acetate and isopropanol. A uniform coating equivalent to% by weight was applied using a pan coater.

Test Example 1 The tablet of Example 1 was measured for the amount of food dye Blue No. 1 dissolved in two liquids of the Japanese Pharmacopoeia by the second method of dissolution test of the Japanese Pharmacopoeia. The concentration of Blue No. 1 was calculated from the absorbance of the spectrophotometer, and the change in the amount of elution was shown in FIGS. From the above results, it was confirmed that the lag time can be adjusted by changing the thickness of the thin portion of the coating film of the water-insoluble and water-permeable substance. On the other hand, a similar test was performed on the tablet of Comparative Example 1, but as shown in FIG.
Unless a part of the coating film of the water-insoluble and water-permeable material is thinned, cracks of different sizes are generated for each tablet in the thin portion of the coating film caused by uncontrollable coating unevenness. It was confirmed that reproducible elution was difficult.

Test Example 2 The tablets of Example 2 were measured for the amount of food dye blue No. 1 dissolved in the Japanese Pharmacopoeia by the second method of dissolution test of the Japanese Pharmacopoeia. The concentration of Blue No. 1 was calculated from the absorbance of the spectrophotometer, and the change in the elution amount is shown in FIG. From the above results, it was confirmed that a similar effect was obtained even when the swelling agent was changed. It was also confirmed that the lag time could be adjusted by changing the type of the swelling agent.

Test Example 3 The dissolution amount of propranolol hydrochloride in the Japanese Pharmacopoeia 2 solution was measured by the third method of dissolution test of the Japanese Pharmacopoeia. The concentration of propranolol hydrochloride was calculated from the fluorescence intensity of the fluorometer, and the change in the elution amount is shown in FIG. From the above results, it was confirmed that a composition having a lag time can be obtained even when the method of forming the thin portion of the coating film of the drug component and the water-insoluble and water-permeable substance is changed. On the other hand, a similar test was performed on the tablet of Comparative Example 2. However, as shown in FIG. 11, control was not performed unless part of the coating film of the water-insoluble and water-permeable substance was thinned. In the thin part of the coating film formed by possible coating unevenness, cracks of different sizes were generated for each tablet, and it was confirmed that reproducible dissolution was difficult.

Test Example 4 The tablets of Example 4 were measured for the amount of food dye Blue No. 1 dissolved in the Japanese Pharmacopoeia 1 solution and the Japanese Pharmacopoeia 2 solution by the second method of the Japanese Pharmacopoeia dissolution test. The concentration of Blue No. 1 was calculated from the extinction coefficient of the spectrophotometer, and the change in the elution amount was shown in FIG.
-14. From the above results, it was confirmed that the dissolution did not occur in the acidic Japanese Pharmacopoeia 1 solution due to the effect of the enteric layer, and it eluted after a certain period of time after immersion in the Japanese Pharmacopoeia 2 solution near neutrality. It was also confirmed that the dissolution behavior in the Japanese Pharmacopoeia 2 solution was not affected by the time of immersion in the Japanese Pharmacopoeia 1 solution.

[Test Example 5] After extirpation, the temperature was kept at 37 ° C.
A suspension of croscarmellose sodium and 3 micrometer fluorescently labeled polystyrene particles or crystalline cellulose and 3 micrometer fluorescently labeled polystyrene particles was injected into the small intestine of a 30 cm rat. Thereafter, physiological saline was flowed at 30 mL / hour, and the effluent was collected over time. After the effluent was filtered with a membrane filter, the number of polystyrene particles on the membrane filter was measured under a microscope, and the results are shown in FIGS. 15 to 16.
From the above results, by using croscarmellose sodium having both characteristics of a swelling agent and a mucoadhesive base in the present invention, compared with the case of using a swelling agent having no mucoadhesive, the drug It was suggested that stagnation at the target site on the gastrointestinal tract for a longer time after release from the composition.

[Brief description of the drawings]

BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a cross-sectional view illustrating a method of applying a uniform thickness to a composition and then masking a part of the surface to reduce the thickness of the part in the manufacturing method of the present invention.

FIG. 2 is a cross-sectional view showing a method of shaving off a part of a coating after applying a coating having a uniform thickness to the composition in the manufacturing method of the present invention.

FIG. 3 In the production method of the present invention, after applying a uniform coating to the composition, a cap or film having the same composition as the coating film is melt-fixed on a part of the surface, and the film other than the part is formed. Sectional drawing which showed the method of thinning.

FIG. 4 is a cross-sectional view showing a method of using a composition having projections on its surface to reduce the thickness of the projections due to friction between the compositions at the time of coating, by using a composition having projections on the surface. .

FIG. 5 is a cross-sectional view illustrating a method of reducing the thickness of a portion of the manufacturing method of the present invention by using a composition having a depression on the surface.

FIG. 6 is a time-dependent change in the average elution amount of the composition of Example 1 in which the thinner portion is a coating equivalent to 2.5% by weight into the Japanese Pharmacopoeia solution.

FIG. 7 is a time-dependent change in the average elution amount of the composition of Example 1 in which a thin portion is a coating equivalent to 3% by weight into two Japanese Pharmacopoeia solutions.

FIG. 8 is a time-dependent change in the amount of each sample eluted in the Japanese Pharmacopoeia solution of the composition of Comparative Example 1;

FIG. 9 is a time-dependent change in the amount of the composition of Example 2 eluted into two Japanese Pharmacopoeia solutions.

FIG. 10 shows the time-dependent change in the average elution amount of the composition of Example 3 into 2 Japanese Pharmacopoeia.

FIG. 11 is a time-dependent change in the average elution amount of the composition of Comparative Example 2 in Japanese Pharmacopoeia 2 liquid.

FIG. 12 shows the change over time in the average elution amount when the composition of Example 4 was immersed in 1st Pharmaceutical Solution for 1 hour and then immersed in 2nd Pharmacopoeia Solution. JP1 and JP2 in the figure indicate the time of immersion in JP1 solution and JP2 solution, respectively.

FIG. 13 is a time-dependent change in the average elution amount when the composition of Example 4 is immersed in JP 1 solution for 4 hours and then immersed in JP 2 solution. JP1 and JP2 in the figure indicate the time of immersion in JP1 solution and JP2 solution, respectively.

FIG. 14 is a time-dependent change in the average elution amount when the composition of Example 4 is immersed in JP 1 solution for 6 hours and then immersed in JP 2 solution. JP1 and JP2 in the figure indicate the time of immersion in JP1 solution and JP2 solution, respectively.

FIG. 15 shows the number of fluorescence-labeled polystyrene particles which were injected into a small intestine of a excised rat by injecting a suspension comprising croscarmellose sodium and fluorescence-labeled polystyrene particles, and which had flowed out from the terminal after a predetermined time.

FIG. 16 shows the number of fluorescence-labeled polystyrene particles which were injected into the small intestine of a excised rat after injecting a suspension composed of crystalline cellulose and fluorescence-labeled polystyrene particles, and which had flowed out from the terminal after a predetermined time.

FIG. 17 is a cross-sectional view of the composition of Examples 1 and 2, wherein 1) is a core containing a main agent and a swelling agent, 2) is a coating film made of a water-insoluble and water-permeable substance, and 3) is 2). Is a portion where the thickness of the coating film is thin.

FIG. 18 is a cross-sectional view of the composition of Example 3, wherein 1) is a core containing a main agent and a swelling agent, 2) is a coating film made of a water-insoluble and water-permeable substance, and 3) is a coating film of 2). The portion 4) having a small thickness of the coating film is a coating film made of an enteric base.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/36 A61K 47/36 47/38 47/38 (72) Inventor Yasuhide Uejima 4 Asahigaoka, Hino-shi, Tokyo 3-2, Teijin Co., Ltd. Tokyo Research Center F-term (reference) 4C076 AA42 AA95 BB01 BB05 BB35 CC01 CC03 CC04 CC05 CC06 CC07 CC11 CC15 CC22 CC27 CC30 CC50 DD05V DD25V DD43V DD55V EE06 EE09 EE11 EE16 EE32 EE24 EE32 EE24 EE26 EE37 EE38 EE41 EE42 EE45 EE48 EE57 EE60 FF06 FF25

Claims (23)

[Claims] 1. A pharmaceutical composition comprising a core composed of a drug and a swelling agent, and a coating layer surrounding the core, wherein (a) the coating layer is a water-insoluble and water-permeable substance A part of the coating film layer is (1) thinner in film thickness than the other coating film layer portions, or (2) accompanying the swelling of the nucleus as compared with the other coating film layer portions. The composition has a low breaking strength against stretching of the coating film layer to be applied, and (a) after being orally administered to a warm-blooded animal,
A pharmaceutical composition, wherein after a predetermined time, a part of the coating film layer is cracked by swelling of the swelling agent, and the drug in the nucleus is released outside the composition. 2. The method according to claim 1, wherein said swelling agent is carmellose, carmellose sodium, croscarmellose sodium, carmellose calcium, wheat starch, rice starch, corn starch, potato starch, partially pregelatinized starch, hydroxypropyl starch, carboxymethyl starch sodium. One or more swelling agents selected from the group consisting of crospovidone, crospovidone, crystalline cellulose, methylcellulose, polyacrylic acid and its derivatives and their copolymers, polymethacrylic acid and its derivatives and their copolymers. The pharmaceutical composition according to claim 1. 3. The water-insoluble and water-permeable substance is selected from the group consisting of cellulose derivatives such as ethyl cellulose and cellulose acetate, polyacrylic acid and derivatives thereof, and copolymers thereof, and derivatives of polymethacrylic acid such as aminoalkyl methacrylate copolymers and the like. Copolymer,
One or two selected from the group consisting of polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, shellac, a complex of polyacrylic acid and polyethylene glycol, a complex of polyacrylic acid and polyvinylpyrrolidone, and a complex of polylysine and alginic acid The pharmaceutical composition according to claim 1, which is the above substance. 4. The method according to claim 1, wherein the thickness of a part of the coating film layer is thinner than that of the other coating film layers, after the composition is uniformly coated, a part of the surface is masked. A method of reducing the thickness of a part, a method of shaving off a part of a coating after applying a uniform thickness to the composition, and a coating film on a part of the surface after applying a uniform thickness to the composition A method of melting and fixing a cap or a film having the same composition as described above to reduce the thickness of the portion other than the portion, and using a composition having a projection on the surface, the projection portion is scraped off by friction between the compositions at the time of coating, thereby forming a film on the portion. The pharmaceutical composition according to claim 1, which is achieved by a method of reducing the thickness or a method of reducing the thickness of the portion by using a composition having a concave surface. 5. The composition according to claim 1, wherein a portion of the coating film layer has a composition in which the breaking strength against stretching of the coating film layer accompanying the swelling of the nucleus is lower than that of the other coating film layer portions. The pharmaceutical composition according to claim 1, which is achieved by localizing a plasticizer in the coating film layer. 6. The pharmaceutical composition according to claim 1, wherein the core further contains 50% by weight or less of a foaming agent based on the weight of the core. 7. The foaming agent is one or more foaming agents selected from the group consisting of tartaric acid, sodium bicarbonate, potato starch, citric anhydride, sodium lauryl sulfate, and lauromacrogol. Item 14. The pharmaceutical composition according to Item. 8. The method according to claim 1, wherein the nucleus is composed of two or more parts, and the drug constituting the nucleus and the swelling agent are not present in the same part. The pharmaceutical composition according to any one of the preceding claims. 9. The pharmaceutical composition according to any one of claims 1 to 8, further comprising a water-permeability controlling film made of a water-soluble substance on the coating film. 10. The water-permeability controlling membrane is made of a cellulose derivative such as hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carmellose sodium, polyvinylpyrrolidone, polyethylene glycol, polyacrylic acid and derivatives thereof and copolymers thereof. , Polymethacrylic acid and its derivatives and copolymers thereof,
The pharmaceutical composition according to claim 9, comprising one or more water-soluble substances selected from the group consisting of polyvinyl alcohol. 11. The water-permeability controlling membrane is formed from hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, cellulose acetate trimellitate, aminoalkyl methacrylate copolymer, methacrylic acid copolymer. 10. The pharmaceutical composition according to claim 9, comprising one or more enteric substances selected from the group consisting of: 12. The pharmaceutical composition according to claim 1, wherein the drug is present in the nucleus as sustained-release fine particles. 13. The granules comprising a water-soluble base, a water-permeable base or a biodegradable base and a drug, or a water-soluble base or a biodegradable base. The pharmaceutical composition according to claim 12, which is a coated particle comprising a coating layer containing an agent and a drug coated on the clothing layer. 14. The water-soluble base and the water-permeable base are preferably hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carmellose sodium, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxylate Methyl ethyl cellulose, cellulose acetate phthalate, cellulose acetate trimellitate,
Ethyl cellulose, cellulose derivatives such as cellulose acetate, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, gelatin, shellac, polyacrylic acid and derivatives thereof and copolymers thereof,
One or more selected from the group consisting of polymethacrylic acid and its derivatives and copolymers thereof, a complex of polyacrylic acid and polyethylene glycol, a complex of polyacrylic acid and polyvinylpyrrolidone, and a complex of polylysine and alginic acid. Item 14. The pharmaceutical composition according to Item 13. 15. The biodegradable base is one or more biodegradable bases selected from the group consisting of polyglycolic acid, polylactic acid, and lactic acid / glycolic acid copolymer. The pharmaceutical composition according to any one of the preceding claims. 16. The composition according to claim 1, further comprising a mucoadhesive substance in the nucleus. 17. The mucoadhesive base comprises carmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, methylethylcellulose, polyacrylic acid and its copolymers, polyethylene glycol and its copolymers, chitosan and sodium alginate. 2. One or more mucoadhesive bases selected from the group.
Item 7. The pharmaceutical composition according to Item 6, 18. The pharmaceutical composition according to claim 16, wherein the swelling agent is croscarmellose sodium. 19. When the drug is released outside the composition, at least 30%, preferably at least 50%, of the drug content is:
The pharmaceutical composition according to any one of claims 1 to 18, which is released within one hour from the start of release. 20. After oral administration to a warm-blooded animal, the pharmaceutical composition passes through the stomach in the body of the warm-blooded animal, and releases the drug outside the pharmaceutical composition 30 minutes or more after reaching the small intestine. The pharmaceutical composition according to any one of claims 1 to 19, wherein 21. The drug, wherein the drug is an anti-inflammatory steroid, an analgesic / anti-inflammatory, an antitussive expectorant, an antihistamine, an antiallergic,
Antirheumatic drugs, bronchodilators, antiemetics, migraines, sleep inducers, sleep sedatives, vitamins, sex steroid hormones, antitumor drugs, vasopressors, antithrombotics, antianxiety / psychotropic drugs, anti 21. One or more drugs selected from the group consisting of epilepsy drugs, anti-ulcer drugs, analgesics, immunosuppressants, vaccines, toxoids and peptide / proteinaceous drugs. The pharmaceutical composition according to any one of the preceding claims. 22. The composition according to any one of claims 1 to 20, wherein the drug is a drug that acts via the Peyer's patch of the small intestine. 23. A drug acting through the Peyer's patch of the small intestine, wherein the drug is an anti-inflammatory steroid drug, a sex steroid hormone drug,
23. The pharmaceutical composition according to claim 22, which is one or more drugs selected from the group consisting of immunosuppressants, vaccines, toxoids, and peptide / proteinaceous drugs.