WO1993012818A1

WO1993012818A1 - Pharmaceutical preparation for topical application

Info

Publication number: WO1993012818A1
Application number: PCT/JP1992/001684
Authority: WO
Inventors: Koichi Oshima; Yasuo Morita; Sumie Seki; Tadanori Morikawa; Eiichi Mafune
Original assignee: Daiichi Pharmaceutical Co., Ltd.; Fuji Yakuhin Kogyo Kabushiki Kaisha
Priority date: 1991-12-27
Filing date: 1992-12-22
Publication date: 1993-07-08
Also published as: JPH05246841A

Abstract

A pharmaceutical preparation for topical application comprising a drug held by a highly water-absorbent polymer. It can hold a drug stably, facilitates the regulation of a dose, and is capable of sustained release. Since it is nonsticky and does not exude, the affected part can be kept clean and the removal of excessive base is unnecessary, thus facilitating nursing and widening the application field of the preparation.

Description

Pharmaceutical preparations

Technical field

The present invention provides a topical preparation, more specifically, a drug that is retained in a superabsorbent polymer, is stable, does not stick, or leaks, is easy to remove and clean after application to an affected area, and It relates to a topical preparation that allows easy control of the amount of drug.

Background art

In general, liquids, aerosols, ointments, plasters, cataplasms, vaginals, suppositories, and the like are used to treat skin diseases, vaginal and hemorrhoids, and the like. All of these are preparations in which an appropriate base and drug are uniformly mixed and applied as it is or molded into a fixed shape, or applied by spreading on cloth, paper, or plastic film. .

However, in these conventional preparations, (1) the unstable drug is decomposed by moisture contained in the base, (2) application becomes difficult due to body temperature, exudate, etc. It may cause stickiness or leakage of the base or drug, resulting in uncertain drug dosage. (3) It is difficult to remove the preparation and clean the affected area after removal. (4) Especially for suppositories. However, the method had disadvantages such as difficulty in fixing at the affected part.

Therefore, the stability of the drug is good, it does not have stickiness and does not cause leakage, it is easy to adjust the amount of drug, it is easy to remove and clean after application, and it is easy to use, skin diseases, vaginal diseases, It has been desired to develop a topical preparation that can be used for diseases such as hemorrhoids.

Disclosure of the invention Under such circumstances, the present inventors have conducted intensive studies and found that the drug held in the superabsorbent polymer is unexpectedly released out of the polymer by the moisture absorbed by the superabsorbent polymer. The present inventor has discovered and found that the above problem can be solved by using this, and completed the present invention.

That is, the present invention provides a topical preparation comprising a superabsorbent polymer holding a drug.

In addition, the topical preparation of the present invention refers to a topical preparation used for the treatment of so-called athlete's foot and insects, as well as an external preparation used by coating or pasting for the treatment of ordinary skin diseases. It also includes preparations to be used, or preparations that absorb drugs from mucous membranes such as vaginal preparations, suppositories, nasal absorption preparations, and ear absorption preparations.

The superabsorbent polymer used in the present invention preferably has a water absorption of 50 ml or more per gram of the polymer, and more preferably has a water absorption of 100 ml or more. Examples of such superabsorbent polymers include starches such as starch Z acrylonitrile, starch carboxymethylated starch, celluloses such as cellulose acrylonitrile, carboxymethylated cellulose, polyacrylic acid, polyvinyl alcohol, polyacrylamide, A synthetic polymer such as polyoxyethylene, poly (vinyl alcohol) polyacrylate, polyacrylic acid Z polyacrylamide, polyacrylamide Z polyvinyl alcohol, or a force capable of using any of two or more selected polymers. From the viewpoint of molding processing, polyacryloleic acid ^ m, polyvinyl alcohol-based, polyacrylamide-based, polyoxyethylene-based synthetic polymer, or a mixed polymer of two or more selected from these are preferred. High absorption Commercially available aqueous polymers can be used, such as Lansir-F (Toyobo), Arrasorp (Arakawa Chemical), Wondergel (Kao), San Diego (Sanyo Chemical), Sumikagel (Sumitomo Chemical), Aqualic (Nippon Shokubai Chemical) ), Lansir (Nippon Xelan), etc. can be used.

The form of the superabsorbent polymer is not particularly limited, and may be in the form of a powder, a film, a nonwoven fabric, a fiber, or the like, depending on the purpose of use and the site of use.

The drug used in the present invention is preferably a solid drug at room temperature, and the drug used varies depending on the purpose and site of use. For example, antibiotics, antibacterial agents, antiviral agents, Fungicides, anticancer agents, anti-inflammatory agents, antihistamines, antirheumatic agents, gout treatments, hormones, inotropic agents, antiarrhythmic agents, angina treatment agents, vasodilators, antihypertensive agents, vasopressors, diuretics, bronchodilators Agents, bronchial asthma treatments, respiratory stimulants, antitussives, expectorants, ulcer treatments, antipyretic analgesics, sleeping pills, autonomic nervous system drugs, ENT, dermatological, urinary and reproductive agents And uterus preparations, therapeutic agents for hemorrhoidal diseases, vitamins and the like. One of these drugs can be used as a single agent, or two or more of them can be used as a composite agent. The topical preparation of the present invention may be used, for example, in the form of a powder, film, nonwoven fabric or fiber containing a superabsorbent polymer as it is or appropriately in accordance with its intended use (for example, when it is used in close contact between the hands and toes, a finger pad is used). Shape, vaginal or suppository, tampon-like, nasal-absorbing preparation, nasal plug-like), absorb an aqueous solution of the drug at an appropriate concentration, and then freeze It can be manufactured by removing only water by a method such as drying and keeping the drug uniformly in the superabsorbent polymer. it can.

When the drug to be used is insoluble or hardly soluble in water, the drug is dissolved in an organic solvent such as alcohol and absorbed in a molded superabsorbent polymer. The topical preparation of the present invention can be produced by uniformly retaining the drug in the water-absorbing polymer.

Further, depending on the purpose of use and if necessary, the superabsorbent polymer holding the drug obtained above may be covered with a nonwoven fabric, woven fabric or sheet made of the same or different material on the front and back. It can also be used.

In the present invention, the amount of the drug retained in the superabsorbent polymer depends on the type of the drug, the purpose of use and the site of use, and usually 1〃g to lg, preferably 1 to 1 g of the superabsorbent polymer. It is about 0 g to 50 O mg.

Since the superabsorbent polymer itself absorbs water, the topical formulation of the present invention thus obtained can block the drug from moisture even during storage and stabilize water-unstable drugs. Can keep power.

The topical preparation of the present invention can be used as it is or by cutting it into an appropriate size at the time of use, and applying, pasting or inserting it onto a local disease or site, and exuding the superabsorbent polymer in the topical preparation In addition to absorbing secretory fluid, body fluid, etc., the affected area is kept clean, and even if the absorbed exudate, secretory fluid, body fluid, etc. are minimal, the drug force is released from the topical preparation by this, It can exhibit the effect of making everything.

In addition, the topical preparation of the present invention can be used regardless of whether it is intended for local action or systemic action. Expecting release effect Wear. Furthermore, since the base does not remain in the affected area when removing the topical preparation of the present invention, it is easy to remove and clean the affected area, it can be removed at any time during the course, and emergency treatment is easy. The amount of drug can also be controlled at any time.

In addition, the topical preparation of the present invention may contain one or more drugs suitable for therapeutic purposes, as well as stabilizers (for example, dextrin, dextran, α, β, arcyclodextrin, Hydral talcite, etc.). ), Absorption enhancers (eg, surfactants such as disodium ethylenediaminetetraacetate, tartaric acid, cunic acid, succinic acid, L-ascorbic acid, etc.), preservatives (eg, benzalkonium chloride, benzozetonium chloride, β-1 Naphthol, thimerosal, thymol, etc.), dispersants (eg, lactose, tragacanth powder, starch, precipitated calcium carbonate, etc.), deodorants

(Eg, activated carbon) can be added as appropriate.

BEST MODE FOR CARRYING OUT THE INVENTION

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples. The present invention is not limited thereto.

Example 1

Place the polyethylene sheet (4 cmx 4 cm) 2 0 Omg powdered polyacrylate crosslinking system superabsorbent polymer over, it is a cycle Rick AMP derivative, N ^6, 2 '-0- dibutyryl adeno sheet Hmm 3 ml of an aqueous solution (1 Omg / ml) of 3 ', 5'-cyclic sodium phosphate (generic name: bucladesin sodium, hereinafter abbreviated as DB cAMP) was absorbed. After removing the water by freeze-drying, cover with a polyester non-woven fabric (4 cm x 4 cm), heat seal the lower polyethylene sheet and the four sides, and hold the water-absorbent polymer that holds DB c AMP. A formulation was obtained.

Example 2

A nonwoven fabric containing 70% of a 3 mm x 3 cm acrylyl fiber hydrolyzate superabsorbent polymer (Lancy Lue F, manufactured by Toyobo Co., Ltd.) of 4 mm thickness is placed on polyethylene (4 cm x 4 cm). Then, 3 ml of an aqueous solution of D Be AMP (1 OmgZml) was absorbed. After water was removed by freeze-drying, the polyethylene sheet under the cover was covered with a polyester non-woven fabric (4 cm × 4 cm), and the four sides were heat-sealed to obtain a superabsorbent polymer preparation holding DBcAMP.

Example 3

20 Omg of a powdery polyacrylate crosslinked superabsorbent polymer is placed on a polyethylene sheet (4 cm x 4 cm), and then a synthetic antibacterial agent, sodium-N ^1- (6-methoxy-1 41) 3 ml of an aqueous solution (1 Omg / ml) of a pyrimidinyl) sulfanilamide monohydrate (generic name: sodium sulfamonomethoxin, abbreviated as DMN hereinafter) was absorbed. After water was removed by freeze-drying, the resultant was covered with a polyester nonwoven fabric (4 cm x 4 cm), and the lower polyethylene sheet was heat-sealed on four sides to obtain a superabsorbent polymer preparation retaining DMN.

Example 4

Polyethylene sheet (4 cm x 4 cm) contains 70% of 3 mm x 3 cm acrylyl fiber hydrolyzate superabsorbent polymer (Ransil-1F, manufactured by Toyo Seimitsu Co., Ltd.) of 4 mm thickness Then, 3 ml of an aqueous solution of DMN (1 Omg / ml) was absorbed therein. After removing water by freeze-drying, polyester non-woven fabric (4 cm x 4 cm) Then, the lower polyethylene sheet and the four sides were heat-sealed to obtain a highly water-absorbing polymer preparation retaining DMN.

Example 5

On a polyethylene sheet (4 cm x 4 cm), 20 mg of powdered polyacrylate crosslinked superabsorbent polymer is placed, and a synthetic antibacterial agent (±) — 9-Fluoro-2,3-dihydro-3 —Methyl-1 10— (4-Methyl-1-piperazinyl) -17-oxo-17H-pyrido [1,2,3_de] [1,4] Benzoxazine-16-carboxylic acid (generic name: off 3 ml of an aqueous suspension (1 OmgZm 1) of oral oxacin was absorbed. After removing the water by freeze-drying, the product was covered with a polyester nonwoven fabric (4 cm x 4 cm), and the lower polyethylene sheet and the four sides were heat-sealed to obtain a superabsorbent polymer preparation holding ofloxacin.

Example 6

A nonwoven fabric containing 70% of a 3 mm x 3 cm acrylyl fiber hydrolyzate superabsorbent polymer (Ranchi F, manufactured by Toyobo Co., Ltd.) of 4 mm thickness on a polyethylene sheet (4 cm x 4 cm) It was placed on it, and 3 ml of an aqueous suspension of ofloxacin (1 Omg / ml) was absorbed. After water was removed by freeze-drying, the resulting product was covered with a polyester non-woven fabric (4 cm x 4 cm), and the lower polyethylene sheet and four sides were heat-sealed to obtain a superabsorbent polymer formulation holding ofloxacin. Example 7

Polyethylene sheet (4 cm x 4 cm) contains 70% of a 4 mm thick, 3 cm x 3 cm hydrolyzate of ataryl fiber-based superabsorbent polymer (Lansil-F, manufactured by Toyobo Co., Ltd.) Place the non-woven fabric and Then, 3 ml of an aqueous solution (10 mgZml) of poly [(2-oxo-111-pyrrolidyl) ethylene] diodyne (generic name: povidone) as a disinfectant was absorbed. After water was removed by freeze-drying, the resulting product was covered with a polyester non-woven fabric (4 cm x 4 cm), and the lower polyethylene sheet and four sides were heat-sealed to obtain a superabsorbent polymer formulation that retained povidonoxide.

Example 8

On a polyethylene sheet (4 cm x 4 cm), a non-woven fabric containing 70% of a 4 nun thick, 3 cm x 3 cm acrylic fiber hydrolyzate superabsorbent polymer (Lancele I-F, manufactured by Toyobo Co., Ltd.) Then, 3 ml of an aqueous solution (10 mgXml) of 2-ethoxy-6,9-diaminoacridin lactate hydrate (generic name: acrylinol), which is a disinfectant, was absorbed. After removing water by freeze-drying, it was covered with a polyester non-woven fabric (4 cm x 4 cm), and the lower polyethylene sheet and the four sides were heat-sealed to obtain a highly water-absorbing polymer preparation holding acrynol.

Example 9

Powdered polyacrylate crosslinked superabsorbent polymer is molded into a 3 mm x 30 mm column and absorbs an aqueous solution (0.5 mg / m1) of synthetic calcitonin derivative, elcatonin (0.2 m1). Was. The water was removed by lyophilization to obtain a superabsorbent polymer preparation (vaginal preparation for rats) retaining L-potency.

Example 10

3 mm x 30 mm non-woven fabric containing 70% acryl fiber hydrolyzate-based superabsorbent polymer (Lanseal I-F, manufactured by Toyobo Co., Ltd.) Then, 0.2 ml of an aqueous solution (0.5 mg / m 1) of erutonin, a synthetic calcitonin derivative, was absorbed into the column. Water was removed by freeze-drying to obtain a highly water-absorbing polymer preparation (vaginal preparation for rats) retaining elcatonin.

Test example 1

A storage test was performed on the preparation obtained in Example 1 and the DBC AMP ointment in a constant temperature bath at 40 ° C. After 1 to 3 months, the content of DBcAMP was quantified by liquid chromatography (reverse phase column HPLC, 11 \ detection of 25411111). The results are shown in Table 1. The results in Table 1 show that the product of the present invention has excellent stability of DB c AMP.

table 1

*: DBcAMP ointment: DBcAMP (3%), Macrogol 400 (67%) Macrogol 4000 (28%),

Dextrin α%),

Dry aluminum hydroxide gel (1%) Test Example 2

A drug release test was performed on the preparations obtained in Examples 1 to 7.

Eight Kim towels (Jujo Kimberly Co., Ltd .; 3 cm x 3 cm) were uniformly wetted with 1 ml of water. The preparation obtained in Example 1 was placed on a wet Kim towel and fixed with tape, and the Kim towel was replaced with time. DB c AMP was extracted from each Kim towel and quantified using an ultraviolet absorption spectrophotometer (manufactured by Shimadzu: UV-160, measurement wavelength 254 nm). Was. The formulation obtained in Example 27 was also tested in the same manner as described above. (Measurement wavelength: Example 2: 254 nm, Examples 3 and 4: 264 nm, Hife examples 5 and 6: 287 nm, Example 7: 222 nm)

did.

Table 2

mean ± S.E. (n = 4) Test example 3

A drug release test of the preparation obtained in Example 2 was performed using a rat stratum corneum exfoliation model.

Test method>

Using a male SD rat (body weight 220 270 g), the stratum corneum was separated by repeatedly applying and removing a gum tape to the abdominal skin 20 times under urethane anesthesia. The preparation of Example 2 was stuck to the stratum corneum It was fixed with plaster. At 1, 2, 4, 8, and 12 hours after administration, blood was collected from the jugular vein by heparin, and the amount of unchanged substance in plasma was determined by liquid chromatography (reverse-phase HPLC, 11 ¥ detection of 2541111). did. Further, after the site to which the preparation was applied was wet with physiological saline solution 200 / z 1 in advance, the preparation of Example 2 was applied and fixed with a bandage, and the test was performed in the same manner as described above. Table 3 shows the results.

Table 3

mean ± S.E. (n = 5) Test example 4

A drug release test of the preparations obtained in Examples 9 and 10 was performed using rats.

Test method>

SD female rats 8 weeks old (weight: 130-190 g) were fasted for 24 hours and used. Under Nembutal anesthesia, the preparations obtained in Examples 9 and 10 were vaginally administered, and before the administration and at 1, 2, 3, 4, and 6 hours after the administration, blood samples were collected from the palline at 250 01 each. The a concentration was quantified by calcium C—Test Co. (Wako Pure Chemical Industries, Ltd.). The results are shown in Tables 4 and 5. Table 4

mean soil S. B. (n = 5) Industrial availability

The topical preparation of the present invention can stably hold a drug, easily adjust the amount of a drug, and impart sustained release. In addition, since there is no stickiness or omission, the affected area can be kept clean and it is not necessary to remove excess base material, so that it is easy to receive and can be widely used as a topical preparation.

Claims

Scope of Claim. A topical preparation consisting of a superabsorbent polymer holding a drug.

The superabsorbent polymer is a polymer selected from starch, cellulose, and synthetic polymers or a mixed polymer of two or more polymers, and is in the form of powder, film, nonwoven fabric, or fibrous. A topical formulation according to paragraph 1.

If the drug is an antibiotic / antibacterial agent, anti-viral agent, anti-fungal agent, anti-cancer agent, anti-inflammatory agent, anti-histamine agent, anti-rheumatic agent, gout treatment agent, hormonal agent, inotropic agent, anti-arrhythmic agent, angina treatment agent, vasodilator Agents, antihypertensives, vasopressors, diuretics, bronchodilators, bronchial asthma treatments, respiratory stimulants, antitussives, expectorants, ulcers, antipyretic analgesics, sleeping pills, autonomic nervous system drugs, otolaryngology diseases 2. The topical preparation according to claim 1, wherein the preparation is one or more selected from the group consisting of a preparation, a dermatological preparation, a urinary and reproductive preparation, a uterus preparation, a therapeutic agent for hemorrhoidal disease, and a vitamin.

2. The topical preparation according to claim 1, wherein the superabsorbent polymer is a synthetic polymer, and the drug is a water-unstable drug.

The superabsorbent polymer is a synthetic polymer, and the drug is N ⁶ , 2'-0-dibutyryl adenosine 1 ', 5'-cyclic sodium phosphate (generic name: sodium bucladecin) A topical formulation according to paragraph 1.