JP4239036B2 - Improved pharmaceutical composition - Google Patents

Description

  The present invention relates to a pharmaceutical composition containing a 4-aminoquinoline compound and magnesium chloride.

  The present invention uses the novel pharmaceutical composition of the present invention to treat ocular inflammation due to various etiologies such as immune disease factors, surgery, chemical or physical disorders, or exposure to radiation, infrared or ultraviolet radiation It also relates to the prevention of disorders caused by degenerative degeneration, allergic or infectious pathogenic factors.

  The invention further relates to the composition obtained according to the invention and to the treatment of ocular inflammation with the composition. Ocular inflammation includes dry eye or ocular surface damage.

  Ocular inflammation includes part of the eye or even more extensive inflammation. The causes are inflammation, allergies, immune reactions, sequelae of surgery, injuries and others. Ocular inflammation can cause pain, irritation, and excessive tearing, threatens the visual function of the eye, and may alter the optical properties of the eye. Inflammation may be uveitis or keratoconjunctivitis and may be dry eye or ocular surface damage.

  Accordingly, there is a need for new ophthalmic pharmaceutical compositions that safely or effectively treat or prevent inflammatory conditions in the eye.

The anti-inflammatory properties of antimalarial 4-aminoquinoline drugs are well known. They are not used to treat ocular inflammation. Because of their systemic use due to their high doses, they can cause rare but serious ocular toxicity symptoms such as diaphragm deposition, known as swirl inflammation, foveal reflexes, adaptation disorders, macular disorders and retinopathy. Have been associated. These effects are reversible or irreversible.

  The present invention uses a specific concentration of the composition, in particular, in combination with another predetermined low concentration magnesium chloride to achieve the desired effect and avoids those disastrous side effects due to 4-aminoquinoline.

  The 4-aminoquinoline compounds used in the prior art for ophthalmic pharmaceutical compositions have hitherto been considered effective as therapeutic agents for malaria and rheumatoid arthritis.

  Another prior art teaches that 4-aminoquinoline has a potent anti-inflammatory action and is effective as a therapeutic agent for inflammation (General Reference 1).

  Magnesium chloride is a well-known electrolytic solution. Magnesium chloride, along with other electrolytes, is known for eyewashing during eye surgery.

Some 4-aminoquinoline compounds used with magnesium chloride prevent ocular inflammation by applying this composition before, during and after inflammation, especially in cases such as dry eye and other ocular outer and intermediate membrane inflammation And has been found to be effective in treating.

Prior Art Methods for producing 4-aminoquinoline and derivatives thereof and compositions thereof used in the present invention are disclosed in the following patent documents.

EP Patent 1374867
The use of at least one 4-aminoquinoline derivative to obtain a drug for use in antiretroviral therapy is sensitive and / or resistant to conventional therapies, particularly in the treatment of HIV caused by retroviral strains. The 4-aminoquinoline derivative is chloroquine and / or hydroxychloroquine, and the drug can be administered once or several times a day.

WO patent application 0007601
An ophthalmic composition for simultaneously treating ocular surface inflammation and dry eye and a treatment method using the composition are disclosed. Ophthalmic drugs include tetracycline compounds in aqueous form. The medicament preferably further comprises a deficiency of electrolyte sufficient to maintain or restore normal levels of conjunctival mucosa-containing goblet cells and corneal glycogen. These electrolytes can include potassium, chloride, bicarbonate, sodium, calcium, magnesium and phosphate.

US Patent 6086597
The ophthalmic composition utilized in ophthalmic surgery comprises an aqueous solution of sodium hyaluronate in a concentration range of 18 mg to 40 mg sodium hyaluronate / ml solution and sodium hyaluronate with a molecular mass of 1 × 10 6 to 10 × 10 6 r, M. This composition is administered to the eye as a surgical aid in the manner of performing eye surgery. This composition could also be used in cataract surgery.

US Patent 4421920
4-aminochloroquinoline represented by the chemical formula ## STR1 ## (wherein R.sub.1 represents a hydrogen atom or an alkyl group (1 to 5 carbon atoms), R.sub.2 is optional) Alkyl group (1-5 carbon atoms) substituted with a dialkylamino group, or optionally substituted with one or more carboxy or hydroxy groups, and optionally substituted with a dialkylamino group The alkyl group (which represents 1 to 4 carbon atoms) is an amine represented by the chemical formula ## STR2 ## and chloro-1,2,3,4-tetrahydro represented by ## STR3 ## Produced by concentration with quinoline-4-one and aromatization of tetrahydroquinone. This reaction is carried out in the presence of a ruthenium-based catalyst on the substrate. This 4-aminochloroquinoline product is useful as a drug.

US Pat. No. 5,596,002
A novel aminoquinoline derivative represented by the general chemical formula ## STR1 ## is described. In addition, treatments with malaria pathogens, particularly chloroquine-resistant malaria pathogens of formula 1 or pharmaceutically usable salts and hydrolysable ester compounds are described.

  References are made to the descriptions of 4-aminoquinoline compounds and derivatives that are also useful in the practice of the invention disclosed in these applications and patents.

In a preferred embodiment, the 4-aminoquinoline compounds that can be used in ophthalmic pharmaceutical compositions are mefloquine, quinacrine and cletokin.
US Patent 4421920 (Baudeau Inn) US Patent 5596002 (Hof Heinz) US Patent 5,948,791 (Hof Heinz) EP Patent 1374867 WO Patent 0007601 US Patent 6086597 US Patent 4421920 US Pat. No. 5,596,002 US Patent 5,948,791 Line, RI, 36 BR J RHEUMATOL 799-805 (1997)

  Novel topical pharmaceutical compositions for ocular inflammation such as eye drops and eye ointments administered directly into the subconjunctiva or vitreous are described. This novel composition uses a drug that does not necessarily increase drug plasma levels to make the intraocular level of the active drug in mammals persistent, avoiding problems associated with elevated plasma levels such as drug toxicity.

  Another object of the present invention is to provide long-term stable intraocular levels of long-term 4-aminoquinoline.

  Another object of the present invention is to provide sustained intraocular levels of 4-aminoquinoline without increasing plasma levels.

  These objects of the present invention are achieved by the present invention, and the problems associated with the prior art are that 4-aminoquinoline and magnesium chloride are sprayed or placed in the eye through an absorbent contact lens in the form of eye drops, eye ointments or gels. Overcoming by local or direct administration via a sustained release container for administration or by direct injection into the subconjunctiva or vitreous.

  Suitable compounds for the compositions of the present invention are chloroquine, amodiaquine, isomers or salts thereof and structurally similar compounds and magnesium chloride, salts and structurally similar ones.

  The above “salts” are harmless and pharmaceutically usable salts of the compounds described herein that have the desired pharmaceutical properties in mammals. Methods for producing such salts are known.

  4-Aminoquinoline and magnesium chloride compounds are harmless even when administered directly to the eye. Ocular administration administers the compound at a suitable ophthalmic dosage to maintain the intraocular level of the compound over time. When used in an ophthalmic pharmaceutical composition, the 4-aminoquinolone compound and magnesium chloride are useful for the prevention and treatment of, for example, immune disease factors, surgery, ocular inflammation due to chemical or physical damage, or radiation, infrared or ultraviolet exposure, It is effective in preventing and treating disorders caused by degenerative degeneration, allergic or infectious pathogenic factors.

  Accordingly, the drug substance obtained by the method of the present invention is a novel drug composition and has synergistic properties.

  The ophthalmic pharmaceutical composition of the present invention contains 4-aminoquinoline and a magnesium chloride compound as active ingredients. Prior to describing the present invention in further detail, terms will be defined.

  “Pharmaceutically usable salts” are pharmaceutically usable salts derived from various known organic and inorganic counterions, such as sodium, potassium, calcium, magnesium, ammonium. , Tetraalkylammonium and the like, and when the molecule contains a basic functional group, it includes salts of organic acids or inorganic acids such as hydrochloride, hydrobromide, hydroiodide, tartrate. Among the common salts available are salts such as alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, ammonium salts or alkylammonium salts.

Experiments to prove the synergistic effect of chloroquine and magnesium chloride

Four solutions were prepared.
Solution (1) contained 0.03 gm% of a chloroquine phosphate aqueous solution. Solution (2) contained 0.0003 gm% of a magnesium chloride aqueous solution.
Solution (3) contained 0.03 gm% aqueous chloroquine phosphate solution and 0.003 gm% magnesium chloride aqueous solution.
Solution (4) contained 0.9 gm% sodium chloride as a control.

  Fresh ectodermal cells adhered to the basement membrane were placed on four glass slides.

  The cells of slide number 1 were treated with solution 1.

  Similarly, cells with slide numbers 2, 3, and 4 were treated with solutions 2, 3, and 4.

  The slides were exposed to UV light at a wavelength of 390 nanometer peaks by placing them equidistant from the UV light source so that equal amounts of all cells on the slide were exposed. The exposure time was 10 seconds.

  Slides were stained with Rishmann staining and examined with a microscope.

  The cells were observed for traces of damage by UV light.

  The standard of use was shape homogeneity.

Homogeneous round shape-5 points.
50% or more irregular shape of cells-4 points 80% or more irregular shapes of cells-3 points Cell wall creation and truncation-1 point Cell membrane destruction-0 points

Inter-cell distance Evenly packed cells-5 points Increase inter-cell distance so that half of the cells are in the standard high power microscope field-4 points Process so that one third of the cells are in the field-3 points Enter the field of view Cell zero-0 points

Nuclear vacuole formation Vacuole formation-5 points 50% vacuole formation of cells in the visual field-4 points 80% vacuolation of cells in the visual field-3 points Vacuogenesis of all cells-0 points

  Scores were tabulated and analyzed.

The score is as follows.
Solution 1: 8 points Solution 2: 3 points Solution 3: 15 points Solution 4: 1 point

CONCLUSION Therefore, the photoprotective action of chloroquine phosphate combined with magnesium chloride in the above solution is not a simple addition effect of each effect, but an effect produced by the synergy of both.

  According to the present invention, a novel external pharmaceutical composition for the treatment of ocular inflammation is provided. This composition reacts 4-aminoquinoline and magnesium chloride with water, adjusts the pH with ophthalmically available acids and bases, tonics, antibacterial preservatives, suitable absorption enhancers, stabilizers In addition, a base for inflammation treatment ointment can be included. 4-Aminoquinoline has a concentration of 0.001 nanogram / ml to 1.00 mg / ml and contains 0.0001 to 0.3 gram of magnesium chloride as well as water.

  In the above composition, 4-aminoquinoline is mixed with magnesium chloride with water to form a novel drug compound. 4-Aminoquinoline is chloroquine or a derivative, isomer or salt thereof. 4-Aminoquinoline is hydroxychloroquine sulfate and chloroquine phosphate, and chloroquine phosphate is amodiaquine or a derivative, isomer or salt thereof.

  The 4-aminoquinoline compound is selected from the group consisting of chloroquine phosphate, hydroxychloroquine, chloroquine hydrochloride, N, N dideethylchloroquine, mefloquine and cletokin.

  To the composition is added a tonic such as sorbitol, glycerin and dextrose.

  Antimicrobial preservatives such as parahydroxybenzoate, chlorobutanol, benzyl alcohol, benzalkonium chloride can be added to the composition. A suitable absorption enhancer such as a surfactant or bile acid can be added to the composition. A stabilizer such as an antioxidant such as hydrogen sulfite or ascorbate can be added to the composition. Viscosity enhancing agents such as sodium carboxymethyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone and polyvinyl alcohol can be added to the composition. To this composition can be added carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol or hydroxyethylcellulose or artificial tears as a wetting agent.

  In the present invention, acids and bases that can be used ophthalmically are used for pH adjustment, and tonic agents, bactericidal preservatives, suitable absorption enhancers and stabilizers, and ointment bases prevent protein denaturation due to heat shock. To do.

  The composition can be provided as a suspension, solution, ointment, spray, liposome composition, non-emulsion particle composition, or chitosan particle composition, utilizing a slow release insert or administered via a contact lens. it can.

  The foregoing has provided a detailed description of the preferred embodiment. However, the present invention can be implemented in various other forms. Accordingly, the details of the invention described herein are not intended to limit the invention, which is limited only by the claims.

Claims (13)

An improved pharmaceutical composition for the treatment of ocular inflammation, wherein the concentration of 4-aminoquinoline is from 0.001 nanogram / ml to 1.00 mg / ml, and the concentration of magnesium chloride is from 0.0001 gram to 0.00. A pharmaceutical composition in which 3 g% is dissolved in water and the pH is adjusted with an ophthalmically usable acid or base. The pharmaceutical composition according to claim 1, wherein 4-aminoquinoline is chloroquine or a derivative or isomer or salt thereof.   The pharmaceutical composition according to claim 2, wherein 4-aminoquinoline is hydroxychloroquine sulfate.   The pharmaceutical composition according to claim 2, wherein 4-aminoquinoline is chloroquine phosphate.   The pharmaceutical composition according to claim 4, wherein 4-aminoquinoline is chloroquine phosphate or amodiaquine or a derivative, isomer or salt thereof. The pharmaceutical composition according to claim 1 or 2, wherein the 4-aminoquinoline compound is a compound selected from the group consisting of chloroquine phosphate, hydroxychloroquine, chloroquine hydrochloride, N, N dideethylchloroquine , and cletoquine. object. The pharmaceutical composition according to claim 1 , comprising a tonic that is sorbitol, glycerin and / or dextrose. The pharmaceutical composition according to claim 1 , comprising an antimicrobial preservative which is parahydroxybenzoate, chlorobutanol, benzyl alcohol and / or benzalkonium chloride. The pharmaceutical composition according to claim 1 , comprising an absorption enhancer which is a surfactant or a bile acid. The pharmaceutical composition according to claim 1 , comprising a stabilizer which is bisulfite and / or ascorbate. The pharmaceutical composition according to claim 1 , further comprising a viscosity enhancer which is sodium carboxymethyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone and / or polyvinyl alcohol. The pharmaceutical composition according to claim 1 , comprising a wetting agent which is carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol and / or hydroxyethylcellulose or artificial tears.   The pharmaceutical composition is provided as a suspension, solution, ointment, spray, liposome composition, non-emulsion particle composition, or chitosan particle composition and can be administered using a slow release insert or via a contact lens The pharmaceutical composition according to claim 1.