JP2002241272A - Pharmaceutical formulation composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicinal composition used as a liquid medicine. SOLUTION: This medicinal composition comprises 2-amino-2-[2-(4- octylphenyl)ethyl]propane-1,3-diol or its medicinally acceptable acid adduct, a cyclodextrin compound, and, if necessary, further a saccharide.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD [0001] The present invention relates to an active ingredient comprising 2
A pharmaceutical formulation comprising -amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof. More specifically, the present invention relates to a pharmaceutical composition which can be formulated as a liquid and is suitable for suppressing rejection at the time of organ (kidney, liver, heart, small intestine, etc.) or bone marrow transplantation or maintaining immunotherapy or treating autoimmune diseases.

[0002]

2. Description of the Related Art 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof is disclosed, for example, in International Publication WO94 / 08943. It is known to be useful as an inhibitor of rejection in organ or bone marrow transplantation and as a therapeutic agent for various autoimmune diseases such as psoriasis and Behcet's disease and rheumatic diseases.

When these compounds are administered, for example, to a patient immediately after organ or bone marrow transplantation, oral administration is difficult, and it is necessary to rapidly develop the medicinal effect. Under such circumstances, provision of injections has been desired. In addition, treatment with eye drops is suitable for eye diseases, and it is desired to provide a liquid preparation suitable for the formulation. By the way, the above-mentioned patent application discloses that it can be used as an injection and that its specific formulation uses polyethylene glycol and ethanol as a dissolving agent.

[0004]

However, when polyethylene glycol is used, there are problems of local irritation and hemolysis due to the use of polyethylene glycol. Therefore, it is an object of the present invention to provide a pharmaceutical composition that is easy to produce, has reduced side effects such as hemolysis, and has little local irritation.
(4-octylphenyl) ethyl] propane-1,3-
It is an object of the present invention to provide a pharmaceutical composition suitable for a solution containing a diol or a pharmaceutically acceptable acid addition salt thereof.

[0005]

SUMMARY OF THE INVENTION The present inventors have proposed cycloaddition of 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof. By blending dextrins, 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1 is easy to formulate, reduces side effects such as hemolysis, and has little local irritation. It has been found that a pharmaceutical composition suitable for a liquid preparation containing 2,3-diol or a pharmaceutically acceptable acid addition salt thereof is provided, and the present invention has been completed. Furthermore, it has been found that a good liquid composition can be obtained by blending a saccharide, that is, a monosaccharide or a disaccharide.

The present invention has the following gist. (1) A pharmaceutical composition comprising 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof and cyclodextrins. (2) The pharmaceutical composition according to the above (1), wherein the cyclodextrin is a natural cyclodextrin, a branched cyclodextrin, an alkylcyclodextrin, or a hydroxyalkylcyclodextrin. (3) The pharmaceutical composition according to the above (1), comprising a saccharide. (4) The pharmaceutical composition according to the above (3), wherein the saccharide is a monosaccharide or a disaccharide. (5) The pharmaceutical composition according to the above (3) or (4), wherein the saccharide is D-mannitol, glucose, D-xylitol, D-maltose, D-sorbitol, lactose, fructose or sucrose.

[0007]

DETAILED DESCRIPTION OF THE INVENTION 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof, which is a component of the present invention, is as follows: It is produced by the method described in International Publication WO94 / 08943, and is preferably 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol hydrochloride (hereinafter referred to as the present compound). ).

The amount of 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof is based on the total weight of the composition. The content is preferably 0.01 to 20% by weight, particularly preferably 0.1 to 10% by weight. The cyclodextrins used in the present invention include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, dodecakis-2,6-
O-methyl-α-cyclodextrin, tetradecakis-2,6-O-methyl-β-cyclodextrin, hexadecakis-2,6-O-methyl-γ-cyclodextrin, tetradecakis-2,6-O-ethyl-β -Cyclodextrin, α-cyclodextrin partially etherified by a 2-hydroxypropyl group, 2-
Β-cyclodextrin (HP-β-CyD) partially etherified with a hydroxypropyl group, or branched α-cyclodextrin or β-cyclodextrin in which glucose or maltose is α-1,6 glucoside-linked. The amount thereof is preferably 1 to 50 times, especially 10 to 30 times the amount of the present compound.

[0009] The amount of the saccharide used in the present invention is 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof, especially The amount is preferably 1-fold to 100-fold, especially 5-fold to 80-fold the amount of the compound. The pharmaceutical form of the pharmaceutical composition of the present invention is a liquid, specifically, an injection, an eye drop, a nasal drop, an ear drop, a drop, a liquid for oral administration, a liquid for inhalation, and a lotion. Liquids and the like, preferably injections (intravenous, subcutaneous, intramuscular, etc.), eye drops and infusions. These formulation forms are suitably selected according to the indication, its symptoms, the sex and age of the patient, the place of application, etc.
Formulated by methods known to those skilled in the art.

[0010] In the composition of the present invention, in addition to the above components,
For example, a solvent, a tonicity agent, a pH adjuster, a buffer, an antioxidant, a thickener, a surfactant, a preservative, a humectant, a fragrance, a coloring agent and the like can be appropriately contained. Also, these additives
When the composition of the present invention is formulated, it can be blended. In the composition of the present invention, 2-amino-2- [2-
(4-octylphenyl) ethyl] propane-1,3-
The diol or a pharmaceutically acceptable acid addition salt thereof, particularly the present compound, can also be used as a sterile solid such as a lyophilized product. For example, 2-amino-2- [2-
(4-octylphenyl) ethyl] propane-1,3-
A solution obtained by dissolving a diol or a pharmaceutically acceptable acid addition salt thereof, particularly the present compound, in purified water is subjected to aseptic filtration, filled in a vial, and then freeze-dried in vacuo to give a freeze-dried product. It may be sometimes dissolved in an aqueous solution containing the cyclodextrin used in the present invention and, if necessary, a saccharide. These lysates are 2-amino-2- [2-
(4-octylphenyl) ethyl] propane-1,3-
The diol or a pharmaceutically acceptable acid addition salt thereof, in particular, is used in an amount of 5 to 2000 times the amount of the present compound. In addition,
The dissolving solution may contain a solvent, an isotonic agent, a solubilizing agent, a buffer, a preservative,
H regulators, antioxidants, thickeners, surfactants, fragrances and colorants can be added. The lyophilized product,
Usually, it is filled in a vial, replaced with nitrogen, sealed with a rubber stopper, and sealed with aluminum, so that it can be stored at room temperature for a long period of time. Such a freeze-dried product is 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof. It can also be prepared in the same manner as described above from an aqueous solution obtained by mixing dextrins and, if necessary, saccharides.

The composition of the present invention can be used as a liquid preparation, particularly for suppressing rejection after organ or bone marrow transplantation, maintaining immunotherapy, eye diseases such as Behcet's disease or uveitis, psoriasis, atopic dermatitis, contact It can be used for treatment of dermatitis including dermatitis and allergic dermatitis. More specifically, the external preparation of the present invention can be used for prevention or treatment of various indications (immunosuppression in organ or bone marrow transplantation, various autoimmune diseases, various allergic diseases, etc.) conventionally performed with oral preparations. it can. That is, the composition of the present invention can be used as a liquid preparation for organ or tissue transplantation (eg, heart, kidney, liver, lung, bone marrow, cornea, pancreas, small intestine, limb,
Transplantation of muscle, nerve, fatty marrow, duodenum, skin, pancreatic islet cells, etc., including xenograft), graft-versus-host (GvH) disease by bone marrow or small intestine transplantation, autoimmune disease, for example, chronic Rheumatoid arthritis, systemic lupus erythematosus, nephrotic syndrome lupus, Hashimoto goiter, multiple sclerosis, myasthenia gravis, type I diabetes, type II adult-onset diabetes, uveitis, nephrotic syndrome, steroid dependence and steroids It can be used for the treatment and prevention of resistant nephrosis, palmar plantar pustulosis, allergic osteomyelitis, glomerulonephritis and the like, and infections caused by pathogenic microorganisms. Also, the onset of inflammatory, proliferative and hyperproliferative skin diseases, and immune-mediated diseases in the skin, such as psoriasis, psoriatic arthritis, atopic eczema (atopic dermatitis), contact dermatitis, and even eczema dermatitis , Seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa,
It can also be used to treat urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, acne, alopecia areata, eosinophilic fasciitis and atherosclerosis. The compositions of the present invention more particularly treat female or male pattern baldness or senile alopecia by preventing hair loss, forming hair buds and / or developing and growing hair. It can be used to perform hair restoration. The compositions of the present invention may be used for respiratory diseases such as sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia and reversible obstructive airway diseases such as bronchial asthma, pediatric asthma, allergic asthma, endogenous asthma,
It is also applicable to the treatment of conditions such as extrinsic and dusty asthma, especially asthma, including chronic or refractory asthma (eg, late onset and airway hyperresponsiveness), bronchitis and the like.
The compositions of the present invention can also be used to treat liver damage associated with ischemia. In addition, certain eye diseases, such as conjunctivitis, keratoconjunctivitis, keratitis, spring catarrh, uveitis associated with Behcet's disease, keratitis, herpes keratitis, keratoconus, corneal epithelial degeneration, corneal vitiligo, ocular pemphigus , Moren's ulcer, scleritis, Graves' eye disease, severe intraocular inflammation and the like.
The compositions of the present invention may also provide inflammation of mucosa or blood vessels (eg, leukotriene B4 mediated disease, gastric ulcer, vascular injury resulting from ischemic disease and thrombotic disease, ischemic bowel disease, inflammatory bowel disease (eg, Crohn's disease and Ulcerative colitis, necrotizing colitis), intestinal damage associated with burns, and the like.The composition of the present invention can be used for interstitial nephritis, goodpasture syndrome, hemolytic uremic syndrome and diabetic nephropathy Renal diseases such as; polymyositis,
A neurological disease selected from Guillain-Barre syndrome, Meniere's disease, and radiculopathy; endocrine disorders such as hyperthyroidism and Basedow's disease;
Blood diseases such as aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, granulocytopenia and lack of erythropoiesis; bone diseases such as osteoporosis; sarcoidosis, pulmonary fibrosis and idiopathic Respiratory diseases such as interstitial pneumonia; dermatoses such as dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T-cell lymphoma; arteriosclerosis, aortitis, polyarteritis nodosa And cardiovascular diseases such as cardiomyopathy; collagen diseases such as scleroderma, Pegner's granulomas and Sjogren's syndrome; steatosis; eosinophilic fasciitis; periodontal disease; nephrotic syndrome; Can also be used in the treatment or prevention of The composition of the present invention may be an intestinal inflammation / allergy such as Coeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; and food-related allergic diseases, It is also suitable for the prevention or treatment of symptoms that are not directly related to the tract, such as migraine, rhinitis and eczema. The compound is
Due to its ability to promote liver regeneration and / or promote hepatocyte hypertrophy and hyperplasia, the compositions of the present invention may be used to treat immunogenic diseases such as autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis. Including chronic autoimmune liver disease), partial hepatectomy, acute liver necrosis (eg, necrosis due to toxins, viral hepatitis, shock or hypoxia), viral hepatitis B, non-A / non-B hepatitis and cirrhosis For the treatment and prevention of liver diseases such as
The composition of the present invention can also be used as a composition for an antibacterial agent, and thus can be used for treating diseases caused by pathogenic microorganisms and the like. Further, the composition of the present invention may be used for malignant rheumatoid arthritis, amyloidosis, fulminant hepatitis, Shy-Drager syndrome, pustular psoriasis, Behcet's disease, systemic lupus erythematosus, endocrine ophthalmopathy, progressive systemic sclerosis,
Mixed connective tissue disease, aortitis syndrome, Wegener's granuloma, active chronic hepatitis, Evans syndrome, hay fever, idiopathic hypoparathyroidism, Addison's disease (autoimmune adrenalitis), autoimmune orchitis, self Immune ovitis, cold agglutinin, paroxysmal cold hemoglobinuria, pernicious anemia, adult T-cell leukemia, autoimmune atrophic gastritis, lupoid hepatitis, tubulointerstitial nephritis, membranous nephritis, muscular atrophy It can be used for prevention or treatment of lateral sclerosis, rheumatic fever, post-myocardial infarction syndrome, and sympathetic ophthalmitis.

The composition of the present invention can be optionally used together with other immunosuppressants, steroids (prednisolone, methylprednisolone, dexamethasone, hydrocortisone, etc.) or nonsteroidal anti-inflammatory drugs. Particularly preferred as other immunosuppressants are selected from azathioprine, brequinar sodium, deoxyspargarine, mizoribine, mycophenolic acid 2-morpholinoethyl ester, cyclosporin, rapamycin, tacrolimus hydrate.

The composition of the present invention may vary depending on the indication, its symptoms, the sex and age of the patient, the place of application, and the like.
By administering or applying the composition containing 001 to 10% by weight once or several times a day (for example, 2 to 5 times), a clinically favorable effect can be exhibited.

[0014]

The present invention will be described in more detail with reference to the following examples. In the following examples, unless otherwise specified.
All percentages are based on weight. Example 1 An injection preparation or eye drops containing the present compound having the following composition was produced.

The present compound 0.1% α-cyclodextrin 1.0% D-mannitol 5.0% The above composition is dissolved in sterile water for injection, and the total amount is 10 ml.
Injection or eye drops. If necessary, ordinary additives such as a preservative may be added.

Example 2 An injection preparation or eye drops containing the present compound having the following composition was prepared. This compound 0.1% β-cyclodextrin partially etherified with 2-hydroxypropyl 1.0% D-mannitol 5.0% The above composition was dissolved in sterile water for injection to a total volume of 10 ml.
Injection or eye drops. If necessary, ordinary additives such as a preservative may be added.

Example 3 An injection or eye drop containing the present compound having the following composition was produced. The present compound 0.1% α-cyclodextrin 1.0% The above composition is dissolved in sterile water (where necessary, a usual additive such as a preservative can be added).
0 ml into a vial, freeze-dried according to a conventional method,
Make injections or eye drops.

Example 4 An injection preparation or eye drops containing the present compound having the following composition was produced. This compound 0.1% β-cyclodextrin partially etherified with 2-hydroxypropyl 1.0% The above composition is sterilized with water. (If necessary, usual additives such as a preservative may be added.) And after aseptic filtration, the total amount is 1
0 ml into a vial, freeze-dried according to a conventional method,
Make injections or eye drops.

Example 5 An injection preparation or eye drops containing the present compound having the following composition was produced. This compound 0.1% β-cyclodextrin partially etherified with 2-hydroxypropyl 2.0% Sodium chloride 0.9% The above composition was dissolved in sterile water for injection to make a total volume of 10 ml.
Injection or eye drops. If necessary, ordinary additives such as a preservative may be added.

Experimental Examples The preparations of Examples 1 and 2 were compared with Yakuyasu No. 2 (Test Method for Local Injury Local Injury (Draft), January 1, 1979).
A sample solution was prepared according to the Ministry of Health and Welfare Pharmaceutical Affairs Bureau on February 2 and the method of Inglot et al.
As a result of measuring the absorbance at 540 nm according to the method described in Vol. 17, 269 (1968), it is found that the preparations of Examples 1 and 2 have significantly reduced hemolysis.

For the formulation of Example 1, 5 weeks old LEW
Rats were repeatedly intravenously administered for 5 days, and the presence or absence of local irritation was confirmed by using the index of the swelling ratio of the tail {(tail diameter of the drug-administered group−diameter of the control tail)} {diameter of the control tail × 100} as an index. As a result, in Example 1, it was 0%, and Example 1
It is found that the preparation of the present invention does not show local irritation.

[0022]

EFFECT OF THE INVENTION 2-Amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof, cyclodextrins and, if necessary, saccharides Is easy to formulate, side effects such as hemolysis are reduced, and 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3 is less local irritant. A pharmaceutical composition suitable for a solution containing a diol or a pharmaceutically acceptable acid addition salt thereof is provided.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Tsuneo Fujii 955 Komatsuri, Yoshitomi-cho, Yoshitomi-gun, Fukuoka Prefecture Inside the Pharmaceutical Technology Center, Yoshitomi Pharmaceutical Co., Ltd. No. 25 Yoshitomi Pharmaceutical Co., Ltd.Drug Discovery Research Laboratories (72) Inventor Kenji Chiba 955 Kozai, Yoshitomi-cho, Chikugami-gun, Fukuoka F-term in Development Laboratory, Yoshitomi Pharmaceutical Co., Ltd. CC07 CC10 CC11 CC14 CC15 CC16 CC17 CC18 CC21 CC31 DD23 DD38 DD67 EE39W FF56 FF67 4C206 AA01 FA08 KA01 MA02 MA03 MA05 MA36 NA06 ZA02 ZA08 ZA22 ZA33 ZA36 ZA45 ZA51 ZA55 ZA59 ZA66 ZA67 ZA69 ZA69 ZA69 ZA69 ZC35

Claims (5)

[Claims] 1. A pharmaceutical composition comprising 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof and cyclodextrins. 2. The pharmaceutical composition according to claim 1, wherein the cyclodextrin is a natural cyclodextrin, a branched cyclodextrin, an alkylcyclodextrin or a hydroxyalkylcyclodextrin. 3. The pharmaceutical composition according to claim 1, comprising a saccharide. 4. The saccharide is a monosaccharide or a disaccharide.
A pharmaceutical composition according to claim 1. 5. The method according to claim 1, wherein the saccharide is D-mannitol, glucose, D-mannitol.
-Xylitol, D-maltose, D-sorbitol,
The pharmaceutical composition according to claim 3 or 4, which is lactose, fructose or sucrose.