JPH0748246A - Sustained release injection agent - Google Patents

Abstract

PURPOSE:To provide a sustained release injection agent comprising a solution containing a medicine, a dissolving agent capable of dissolving the medicine and incompatible with a fatty or oily base agent, and the fatty or oily base agent, containing the solution in a state dispersed as solution drops in the fatty or oily base agent, and capable of being maintained in a constant concentration in blood for a long period. CONSTITUTION:A medicine such as an anticancer agent, antipyretic analgestic antiphlogistic agent, antihypertensive, hyperlipemia-improving agent, arteriosclerosis, antiallergic agent, cholecystokinin (CCK)-antagonizing substance or immunosuppresant is dissolved in a dissolving agent (e.g. propylene glycol) capable of dissolving the medicine and incompatible with fatty or oily base agents, heated at 80 deg.C, mixed with hydroxypropyl cellulose as a thickening agent, furthermore mixed with the fatty or oily base agent comprising the mixture of bleached beewax, white petrolatum and liquid paraffin, and subsequently cooled to provide the objective sustained release injection agent in which the medicine solution is dispersed as solution drops in the fatty or oily base agent and which can maintain medicine in a constant concentration for a long time and persist the medicinal effect for the elongated action time of the medicine.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a sustained release injection. More specifically, the invention relates to the urethra, bladder, vagina, ear,
The present invention relates to a sustained-release injection which can be applied to all body cavities other than the oral cavity such as the nose or rectum, has excellent sustained-release property and sustainability, and can significantly suppress the occurrence of side effects.

[0002]

2. Description of the Related Art Conventional injections are injected into the urethra, bladder, vagina, ear, nose or rectum to cleanse, antiseptic, disinfect, astringent, corrode, alleviate, anesthetize, cool, It is used for protection purposes. As an injectable agent,
For example, potassium permanganate solution used for cleaning the vagina or bladder, sodium bicarbonate solution used for cleaning the ear canal, nasal cavity or vagina, acrinol solution used for the treatment of pyometra, purulent otitis media, cystitis, urethritis, etc. Silver nitrate solution used for urinary tract cleaning, protein silver solution used for urinary tract cleaning, ephedrine hydrochloride solution used to remove hyperemia and swelling of nasal mucosa, chloramphenicol solution used for sterilization in the ear canal, xylocaine solution applied to the urethra for local anesthesia, Enema preparations for injection into the rectum are known. Each of these injections is a liquid preparation dissolved in water, physiological saline, buffer solution, ethanol, propylene glycol or the like, and optionally contains other additives.

In addition to the injectable preparation, solid suppositories are available as preparations to be inserted into body cavities other than the oral cavity such as the vagina, urethra or anus and applied to the affected area. Suppositories are classified into vaginal suppositories, urethral suppositories, and rectal suppositories, and are used for the purpose of local or systemic action. However, with solid suppositories, defecation is promoted due to the feeling of foreign matter, and it cannot be said that it is suitable as a sustained-release preparation.

[0004]

According to the present invention, a solution comprising a medicine and a dissolving agent which is capable of dissolving the medicine and is incompatible with the oily base, and the oily base Thus, a sustained-release injectable solution is provided, characterized in that the solution is dispersed as a droplet in an oily base.

The sustained-release injection according to the present invention can be applied to all body cavities other than the oral cavity such as urethra, bladder, vagina, ear, nose and rectum. Among these application sites, rectal application for the purpose of systemic action is particularly preferable. As the medicine used in the present invention, all medicines that can be orally or parenterally administered and can be dissolved in a solubilizer can be applied, and it is preferable to apply to medicines for which sustained efficacy is desired. Particularly preferred.

Preferred examples of the drug used in the present invention include anticancer agents (fluorouracil, methotrexate, etc.), antipyretic and analgesic and antiinflammatory agents (indomethacin,
Diclofenac sodium, steroids, etc., antihypertensive agents (nifedipine, nilvadipine, etc.), hyperlipidemia improving / antiarteriosclerotic agents (lecithin, soysterol, etc.), antiallergic agents (chlorpheniramine maleate, etc.), cholecystokinin (CCK) ) Antagonist [(3S) -1- (2-fluorophenyl) -3,4,6,7-tetrahydro-3-
(2-Indolylcarbonylamino) -4-oxopyrrolo [3,2,1-jk] [1,4] benzodiazepine (FK480 substance), (3S) -1-[(1H-tetrazol-5-yl) methyl] -3- (2-Indolylcarbonylamino) -5-phenyl-1,3-dihydro-
2H-1,4-benzodiazepin-2-one, etc.], immunosuppressant [cyclosporin or its analog, rapamycin or its analog, general formula (I)

[0007]

[Chemical 2]

[Wherein R ¹ and R ² , R ³ and R ⁴ , R
Each adjacent pair of ⁵ and R ⁶ is independently, a) representing two adjacent hydrogen atoms or b) forming another bond with the carbon atom to which it is attached. In addition thereto, R ² may be an alkyl group, R ⁷ represents a hydrogen atom, a hydroxy group, a protected hydroxy group or an alkyloxy group, or, together with R ¹ , represents an oxo group. Maybe,
R ⁸ and R ⁹ independently represent a hydrogen atom, a hydroxy group, R
¹⁰ is a hydrogen atom, an alkyl group, an alkyl group substituted by one or more hydroxy groups, an alkenyl group, an alkenyl group substituted by one or more hydroxy groups, or an alkyl group substituted by an oxo group, and X is an oxo group , (Hydrogen atom, hydroxy group), (hydrogen atom, hydrogen atom) or a group represented by the formula —CH ₂ O—, Y is an oxo group, (hydrogen atom, hydroxy group), (hydrogen atom, hydrogen atom), or a group of the formula N-NR ¹¹ R ¹² or N-oR ^13, R ¹¹ and R ¹² are independently hydrogen atom, an alkyl group, an aryl group or a tosyl group, R ^13,
R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²² and R ²³
Are independently a hydrogen atom or an alkyl group, R ²⁰ and R ²¹ are independently an oxo group, or each independently (R ²⁰
a, a hydrogen atom) and (R ²¹ a, a hydrogen atom), R ²⁰ a and R ²¹ a are independently a hydroxy group, an alkyloxy group or a formula OCH ₂ OCH ₂ CH ₂ OCH ₃
Or R ²¹ a represents a protected hydroxy group, and R ²⁰ a and R ²¹ a may together represent an oxygen atom in the epoxide ring, and n is 1, 2 or 3 Represents

In addition to the above meaning, Y, R ¹⁰ and R ²³ are each a nitrogen atom or a sulfur atom consisting of a saturated or unsaturated 5- or 6-membered ring together with the carbon atom to which they are bonded. And / or may represent a heterocyclic group containing an oxygen atom, and the heterocyclic group is an alkyl group, a hydroxy group, an alkyl group substituted by one or more hydroxy groups, an alkyloxy group, a benzyl group and It may be substituted with one or more groups selected from the group represented by the formula —CH ₂ Se (C ₆ H ₅ ). ] The tricyclo compound shown by these or its pharmaceutically acceptable salt, etc.] etc. are mentioned.

A preferred drug belonging to the above tricyclo compound (I) is 17-allyl-1,14-dihydroxy-
12- [2- (4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl] -23,25-dimethoxy-1
3,19,21,27-Tetramethyl-11,28-dioxa-4-
Azatricyclo (22. 3. 1. 0 ^4,9 ) Octacos-18-
En-2,3,10,16-tetraone (FK506 substance), 1,
14-dihydroxy-12- [2- (4-hydroxy-3-
Methoxycyclohexyl) -1-methylvinyl] -23,2
5-dimethoxy-13,19,17,21,27-pentamethyl-11,2
8-Dioxa-4-azatricyclo [22.3.1.0]
^4,9 ] octacos-18-ene-2,3,10,16-tetraone, 12- [2- (4-acetoxy-3-methoxycyclohexyl) -1-methylvinyl] -17-allyl-1,14-
Dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3, 1
0,16-Tetraone, 17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-
12- [2- [4- (3,5-dinitrobenzoyloxy)-
3-Methoxycyclohexyl] -1-methylvinyl]-
11,28-Dioxa-4-azatricyclo [22.3.1.
0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone, 17-allyl-12- [2- [4-[(-)-2-trifluoromethyl-2-methoxy-2- Phenylacetoxy] -3-methoxycyclohexyl] -1-methylvinyl] -1,14-dihydroxy-23,25-dimethoxy-13,1
9,21,27-Tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone, 17-ethyl- 1,14-Dihydroxy-12- [2- (4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa -4-azatricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone, and 17-
Ethyl-1,14,20-trihydroxy-12- [2- (3,4
-Dihydroxycyclohexyl) -1-methylvinyl]
-23,25-dimethoxy-13,19,21,27-tetramethyl-
11,28-Dioxa-4-azatricyclo [22.3.1.
0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone.

Examples of other drugs include the following patent applications: European Patent Application A-353678, Japanese Patent Application No. 2
-74330, PCT / GB90 / 01262, European Patent Application A-413532, PCT / JP9
1/00314, British patent application 9012963.
No. 6, No. 9014136.7, No. 90144681.2
No. 9014880.0 and 9014881.8
No. 90150988.8, No. 9016115.9.
No. 90166693.5, European patent application A-
323865, A-349061, A-358
No. 508, No. A-364031, No. A-364032
No., A-378317, A-378320, A-378321, A-388153, A-3.
96399, A-396400, A-3995
79, A-403242, A-428365.
No. A-356399, British Patent 222522.
6, European patent application A-402931, A-
427680, A-445975, A-455.
No. 427, A-463690, A-464895.
No., A-466365, A-478235, A-480623, A-509753, A-5.
15071, A-520554, A-5269
34, A-53088, A-532089.
No., A-532088, WO92 / 06992,
No. 92/20688, No. 93/04679, No. 93
/ 05059, 93/04680, US Patent 51
49701, German patent application A-4021404,
A-4028664, A-4028665, A-4028666, A-4028667, A
-4028675, A-4028676, A-
The compounds described in 4028677, A-4028678, A-4039587 and the like can be mentioned.

In the present invention, the medicine is one kind or two kinds.
It may be used in a mixture of two or more kinds, for example, a mixture of two or more kinds having the same or different drug effects, or a drug having a certain drug effect and a drug suppressing the defects or side effects of the drug. The content of the drug in the sustained release infusion is appropriate to be 0.005 to 20% (w / w),
0.02 to 2% (w / w) is preferable.

The solubilizer of the present invention means a drug which can dissolve the drug used and which is incompatible with the oily base and biocompatible. Preferred examples of the solubilizer used in the present invention include organic solubilizers, particularly lower alkanediols (ethylene glycol, propylene glycol, butylene glycol, etc.),
Examples include lower alkylene carbonates (propylene carbonate, ethylene carbonate, etc.), lower alcohols (ethanol, isopropyl alcohol, etc.), and the like. Of these, propylene glycol and propylene carbonate are particularly preferable.
Further, the solubilizer may be used alone or as a mixture of two or more kinds.

The content of the solubilizer in the sustained-release injection is preferably 0.5 to 40% (w / w), and 2 to 20%.
% (W / w) is preferred. As the oily base used in the present invention, an oily base commonly used in the art and harmless to the human body can be applied.

Preferred examples of the oily base include natural waxes (eg, beeswax wax, carnauba wax, etc.), petroleum waxes (eg, solid paraffin, microcrystalline wax, etc.), hydrocarbons (eg, liquid paraffin, white petrolatum, etc.). Yellow petrolatum etc.) and the like. Moreover, it is preferable to use these oily bases in appropriate combination.

The viscosity of the sustained-release injection of the present invention is not particularly limited, but it is preferable that the viscosity is in the range of about 10,000 to 30,000 cp. If desired, a thickener may be added to the sustained-release injectable agent comprising the solution of the drug of the present invention and a dissolving agent and the oily base. Thickeners are particularly preferably used to adjust the sustained release injectables to the desired viscosity, depending on the site of application, the drug used, the solubilizer, the oily base and the like.

As the thickener used in the present invention, a thickener which is generally used in the art to impart viscosity to a liquid and which is harmless to the human body can be applied. Preferred examples of the thickener include hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxypolymethylene, carboxymethyl cellulose, methyl cellulose and the like. Further, the thickener may be used alone or as a mixture of two or more kinds.

The amount of the thickener used is an amount capable of imparting an appropriate viscosity to the injection agent, and is appropriately selected according to the desired viscosity of the injection agent. The sustained-release injectable composition of the present invention can be produced by dissolving a drug in a dissolving agent in advance and then stirring and mixing it with an oil-and-fat base which has been dissolved by heating. When a thickener is further added if desired, the thickener is dissolved in a dissolving agent in advance, and then it is mixed with a dissolving agent in which the drug is dissolved, and then the oily group is dissolved by heating. It is preferably produced by stirring and mixing with the agent.

In the injectable agent thus produced, the viscosity is preferably in the range of about 10,000 to 30,000 cp, and the solution of the drug and the dissolving agent is dispersed as a droplet in the oily base. Further, the sustained-release injectable composition of the present invention may further be used for injection, if necessary, for perfumes, colorants, preservatives, dispersants, absorption promoters such as higher alkenoic acid (eg, oleic acid), and the like. Other additives may be included.

[0020]

In the sustained release injection of the present invention, since the solution of the drug and the dissolving agent is dispersed in the oily base as droplets, the drug is gradually released from the injection and is absorbed. To go. Therefore, there is no rapid increase in blood or tissue concentration in the early stage after administration of the drug, and the occurrence of side effects is suppressed.
In addition, the action time of the drug is extended and the drug effect is sustained.

[0021]

The present invention will be described with reference to the following examples.
However, the present invention is not limited to these.

Example 1 Sustained-release injection containing 10% propylene glycol FK506 substance as a drug, propylene glycol (abbreviated as PG in the following examples) as a dissolving agent, salix beeswax as a fat-and-oil base, white petrolatum and fluid Paraffin mixture, hydroxypropyl cellulose as thickener (abbreviated as HPMC in the following examples)
It was used.

0.5 g of FK506 substance is dissolved in 5 g of PG and heated to 80 ° C. To this solution, 0.2 g of H
PMC in 5 g of PG under bubbling of nitrogen gas, 11
What was melted at 0 ° C. and cooled to 80 ° C. was added. After stirring well, 7 g of white beeswax, white petrolatum 52.
A 10% PG-containing sustained-release injection was prepared by mixing 3 g and 30 g of liquid paraffin and heating and dissolving the mixture, stirring and mixing, and cooling to room temperature. In the prepared sustained-release injectable solution, the dissolution agent dissolving the drug was present as droplets in the oily base. This was confirmed by an optical microscope.

Example 2 Sustained-release injection containing 20% PG FK506 substance was used as a drug, PG was used as a dissolving agent, beeswax beeswax as a fat-and-oil base, a mixture of white petrolatum and liquid paraffin, and HPMC was used as a thickener.

0.5 g of FK506 substance is dissolved in 5 g of PG and heated to 80 ° C. To this solution, 0.4 g of H
PMC in 10 g of PG while bubbling nitrogen gas, 1
What was melted at 10 ° C. and cooled to 80 ° C. was added. After stirring well, 7 g of beeswax and 5 of white vaseline
A mixture of 2.1 g and 20 g of liquid paraffin, which had been heated and dissolved, was added, mixed with stirring, and cooled to room temperature to prepare a sustained release injection containing 20% PG. The prepared sustained-release injectable solution is
It was present as droplets in the oily base. This was confirmed by an optical microscope.

Example 3 In the same manner as in Example 1, 0.1 g of FK480 substance was used in place of 0.5 g of FK506 substance to prepare a sustained release injection. Test 1 (In vivo absorption test) An in vivo absorption test when applied to the rectum was performed using each injectable agent prepared in the example.

As a control, FK506
A PG gel injection prepared by dissolving 0.5 g of the substance and 2.0 g of HPMC in 97.5 g of PG was used. As test animals, 4 SD rats were used for each injection.
As a control (PG gel injectable agent), before gelation,
A predetermined amount was preliminarily taken in a combi-chip for 10 microliters. The injectants prepared in the examples all had a viscosity of about 18,000 cp and could be sampled with a 10 microliter combi-chip.

The sustained-release injectable agent (sustained-release injectable agent of the present invention) and PG gel injectable agent (control) prepared in Examples were each administered at a dose of 1 mg / kg of FK506 substance.
It was administered into the rectum of the rat using a syringe. Before administration,
The femoral artery of the rat was cannulated under ether anesthesia, and 0.25 ml of blood was collected 0.5, 1, 2, 4, 8 and 24 hours after administration.

By subjecting the blood collected as described above to an enzyme immunoassay method using peroxidase as an enzyme (for example, the method described in JP-A-1-92659), the whole blood concentration of the FK506 substance can be determined. It was measured. The pharmacokinetic parameters after administration of the infusion were determined, and the results are shown in Table 1. In Table 1, C _max is the maximum blood concentration, T _{ma x}
Is the time to reach maximum blood concentration after injection, AUC _0-24
Is the area under the blood concentration time curve from 0 to 24 hours after injection.

[0030]

[Table 1]

From Table 1, it is clear that the sustained-release injectable composition of the present invention does not have a rapid increase in blood concentration in the early stage after administration and has a constant blood concentration for a long time. That is,
It is clear that the injectable composition of the present invention has excellent sustained release properties.

[0032]

INDUSTRIAL APPLICABILITY The sustained-release injectable composition of the present invention has an excellent sustained-release property and can gradually release a drug so as to maintain a constant blood concentration for a long time. Therefore, a rapid increase in the blood or tissue concentration in the early stage after administration of the drug is suppressed, whereby the occurrence of side effects can be suppressed. Further, the sustained-release injectable composition of the present invention can prolong the action time of the drug and maintain the drug effect.

The sustained-release injectable composition of the present invention is particularly effective for pharmaceuticals for which sustained drug efficacy is desired. In particular, when compound (I) is used as a drug, its pharmacological action shows that the heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine,
Rejection during transplantation of organs or tissues such as limbs, muscles, nerves, intervertebral discs, trachea; graft-versus-host reaction due to bone marrow transplantation; rheumatoid arthritis, systemic lupus erythematosus, Hashimoto thyroiditis, multiple sclerosis, It is effective in treating and preventing autoimmune diseases such as myasthenia gravis and type I diabetes; and infectious diseases caused by pathogenic microorganisms (eg Aspergillus fumigasis, Fusarium oxysporma, Trichophyton asteroides, etc.).

Furthermore, the preparation of compound (I) is useful for treating and preventing the following diseases. Inflammatory and hyperproliferative skin diseases and immunologically mediated skin diseases (eg psoriasis,
Atopic dermatitis, contact dermatitis, eczema dermatitis, seborrheic dermatitis, lichen planus, pemphigus, chicken pox pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema , Cutaneous eosinophilia, lupus erythematosus, acne and alopecia areata; eye diseases of autoimmune disease (eg keratoconjunctivitis, spring conjunctivitis, Behcet's disease-related uveitis, keratitis, herpes keratitis) , Keratoconus keratitis, corneal epithelial dystrophy, corneal leukoplakia, pemphigus ocularis, moor ulcer, scleritis, Graves eye disorder, Voigt-Koyanagi-Harada syndrome, sarcoidosis, etc.); reversible obstructive airway disease [ Asthma (eg, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dusty asthma), especially chronic or refractory asthma (eg, delayed asthma and airway hyperresponsiveness), and bronchitis, etc.); Mucosa and blood vessels Inflammation (e.g. gastric ulcer, vascular damage caused by ischemia and thrombosis, ischemic bowel disease, enteritis, necrotizing enterocolitis, intestinal damage due to burns, leukotriene B ₄ - mediated diseases); inflammation / allergy of intestine (e.g., pediatric fat Fecal disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; food-related allergic diseases (eg, migraine
Rhinitis and eczema); nephropathy (eg interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome and diabetic nephropathy); neurological disorders (eg polymyositis, Guillain-Barre syndrome, Meniere's disease, polyneuropathy) Flame, polyneuropathy,
Mononeuritis and radiculopathy); endocrine disorders (eg hyperthyroidism and Graves'disease); hematological disorders (eg pure erythroblastosis, aplastic anemia, aplastic anemia, idiopathic thrombocytopenia) Purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia and erythropoiesis); bone disorders (eg osteoporosis); respiratory system disorders (eg sarcoidosis) ), Pulmonary fibrosis and idiopathic interstitial pneumonia); skin disorders (eg,
Dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photosensitivity and cutaneous T-cell lymphoma; cardiovascular diseases (eg,
Arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and cardiomyopathy); collagen disease (eg scleroderma, Wegener's granulomas and Sjogren's syndrome); adiposity; eosinophilic fascia Inflammation; periodontal disease [eg, gum, periodontal, alveolar bone, (dental) cementum damage]; nephrotic syndrome (eg, glomerulonephritis); androgenetic alopecia or senile alopecia; muscular dystrophy; pyoderma And Sézary syndrome; Addison's disease; chromosomal abnormalities (eg Down's syndrome); reactive oxygen mediated diseases [eg organ damage (retention, retention,
Ischemic blood flow damage to organs (heart, liver, kidney, digestive organs, etc.) that occurs during transplantation or ischemic disease (thrombosis, myocardial infarction, etc.): Intestinal disease (eg, endotoxin shock,
Pseudomembranous colitis, drug- or radiation-induced colitis): Renal disease (eg, ischemic acute renal failure, chronic renal failure): Pulmonary disease [eg, pulmonary oxygen or drug (eg, paraquat,
Bleomycin) poisoning, lung cancer, emphysema]: eye disease [eg, cataract, iron deposition disease (iron rust), retinitis,
Pigmentation, senile plaque alteration, vitreous scar, alkaline burn cornea]: dermatitis (eg erythema multiforme, linear immunoglobulin A dermatitis, cement dermatitis): and other diseases [eg gingivitis , Periodontitis, sepsis, pancreatitis, or environmental pollution (eg, air pollution), aging, carcinogens, cancer metastasis, altitude sickness]]; Histamine or leukotriene C ₄ release disease; Behcet's disease (eg,
Intestinal type, vascular type, nerve type, oral cavity, skin, eye, vulva, joint, epididymis, lung, kidney) and the like.

Further, the compound (I) has a hepatic regenerating action and / or a stimulating action of hepatocyte hypertrophy and hyperplasia. Therefore, formulations of these compounds are
Immunogenic diseases (autoimmune liver disease, chronic autoimmune liver disease such as primary biliary cirrhosis or sclerosing cholangitis),
Partial liver resection, acute liver necrosis (eg necrosis due to toxicants, viral hepatitis, shock or anoxia), hepatitis B, non-A non-B hepatitis, cirrhosis (eg alcoholic cirrhosis) and liver dysfunction (eg. , Fulminant hepatitis, late-onset hepatitis, and liver dysfunction that has transitioned from acute to chronic)).

Further, the compound (I) preparations have various chemotherapeutic effects such as potentiation of chemotherapeutic action, prevention and treatment of cytomegalovirus and AIDS virus infection, carcinogenesis inhibitory action and anti-inflammatory action. Useful for.

FK50 which is a representative compound of the compound (I)
The six substances may cause nephrotoxicity depending on the formulation and concentration used, and it is considered to reduce nephrotoxicity by administration of drugs with renal vasodilatory effects such as Ca ²⁺ antagonist, angiotensin II antagonist or endothelin antagonist. Has been done.
Such mitigation is also possible by using the formulations of the present application.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/505 9454-4C 31/55 9454-4C 31/56 9454-4C 31/685 ABX ADN 9454 -4C 38/00 ABC

Claims (11)

[Claims] 1. A solution comprising a drug and a dissolving agent which is capable of dissolving the drug and which is incompatible with the oily base, and an oily base, wherein the solution becomes an oily base. A sustained-release injection characterized by being dispersed as droplets. 2. The content of the drug is 0.00 in the sustained release injection.
The sustained release injection according to claim 1, which is 5 to 20% (w / w). 3. The sustained-release injection according to claim 2, which has a viscosity in the range of about 10,000 to 30,000 cp. 4. The drug has the general formula (I): [Wherein each of the adjacent pairs of R ¹ and R ² , R ³ and R ⁴ , R ⁵ and R ⁶ independently represents a) two adjacent hydrogen atoms, or b) a bond may form another bond between with the carbon atom to which was added thereto, R ² may be an alkyl group, R ⁷ is a hydrogen atom, hydroxy group, protected hydroxy group or an alkyl It may represent an oxy group or an oxo group together with R ¹ , R ⁸ and R ⁹ independently represent a hydrogen atom or a hydroxy group, and R ¹⁰ represents a hydrogen atom, an alkyl group or one or more hydroxy groups. An alkyl group substituted with a group, an alkenyl group, an alkenyl group substituted with one or more hydroxy groups, or an alkyl group substituted with an oxo group, X is an oxo group, (hydrogen atom, hydroxy group) , (Hydrogen atom, hydrogen atom) or a group represented by formula —CH ₂ O—, Y is an oxo group, (hydrogen atom, hydroxy group), (hydrogen atom, hydrogen atom), or formula N—NR ¹¹ R ¹² Or N-
The group represented by OR ¹³ , R ¹¹ and R ¹² independently represent a hydrogen atom, an alkyl group, an aryl group or a tosyl group, and R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ , R ²² and R ²³ are independently a hydrogen atom or an alkyl group, R ²⁰ and R ²¹ are independently an oxo group, or each independently (R ²⁰ a, a hydrogen atom) and (R ²¹ a , Hydrogen atom)
R ²⁰ a and R ²¹ a are independently a hydroxy group, an alkyloxy group or a formula OCH ₂ OCH ₂ C.
The group represented by H ₂ OCH ₃ or R ²¹ a represents a protected hydroxy group, and R ²⁰ a and R ²¹ a may together represent an oxygen atom in the epoxide ring, and n is 1 Represents 2 or 3. In addition to the meanings given above, Y, R ¹⁰ and R ²³ are also a nitrogen atom, a sulfur atom and / or a nitrogen atom consisting of a saturated or unsaturated 5- or 6-membered ring together with the carbon atom to which they are attached. Although it may represent a heterocyclic group containing an oxygen atom, the heterocyclic group may be an alkyl group, a hydroxy group, an alkyl group substituted by one or more hydroxy groups, an alkyloxy group, a benzyl group and a formula —CH 2. ₂ Se (C ₆ H
_It may be substituted with one or more groups selected from the group represented by ₅ ). ] The tricyclo compound represented by or a pharmaceutically acceptable salt thereof, fluorouracil, methotrexate, indomethacin, diclofenac sodium, steroid, nifedipine, nilvadipine, lecithin, or cyclosporine, rapamycin or a derivative thereof. The sustained-release injection according to any one of claims. 5. The medicine is (3S) -1- (2-fluorophenyl) -3,4,6,7-tetrahydro-3- (2.
-Indolylcarbonylamino) -4-oxopyrrolo [3,2,1-jt] [1,4] benzodiazepine, The sustained-release injection according to any one of claims 1 to 3. 6. The content of the solubilizer is 0.5 in the sustained release injection.
The sustained-release injectable composition according to any one of claims 1 to 5, which has a content of -40% (w / w). 7. The sustained-release injection according to any one of claims 1 to 6, wherein the solubilizer is a lower alkanediol, a lower alkylene carbonate or a lower alcohol. 8. The sustained-release injection according to claim 7, wherein the dissolving agent is propylene glycol or propylene carbonate. 9. The sustained-release injection according to claim 1, wherein the oily base is a natural wax, a petroleum wax, a hydrocarbon or a mixture thereof. 10. The sustained-release injection according to any one of claims 1 to 9, which further comprises a thickener. 11. The sustained-release injection according to claim 10, wherein the thickener is hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxypolymethylene, carboxymethylcellulose or methylcellulose.