WO1999011270A1 - Pharmaceutical compositions for the treatment of ocular inflammations comprising dexamethasone palmitate - Google Patents
Pharmaceutical compositions for the treatment of ocular inflammations comprising dexamethasone palmitate Download PDFInfo
- Publication number
- WO1999011270A1 WO1999011270A1 PCT/IL1998/000411 IL9800411W WO9911270A1 WO 1999011270 A1 WO1999011270 A1 WO 1999011270A1 IL 9800411 W IL9800411 W IL 9800411W WO 9911270 A1 WO9911270 A1 WO 9911270A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dexamethasone
- treatment
- oil
- ester
- composition
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention provides a novel formulation for the treatment of ocular inflammations and its use.
- oil-in water type emulsions increase in importance as vehicles for delivery of hydrophobic drugs, for example the fat emulsion described in EP 315079.
- U.S. Patent 4,340,594 describes a parenterally administered fat emulsion containing a steroid having an anti-inflammatory activity, inter alia dexamethasone palmitate.
- the fat emulsions described therein are useful in the treatment of rheumatism, immunological hemolytic anemia, idiopathic thrombocytopenic purpura, Paget disease or in conjunction with kidney transplantation.
- Dexamethasone palmitate works as a prodrug since it is hydro- lyzed in the body by esterases into its bioactive metabolite, dexamethasone. Nonetheless, dexamethasone palmitate has some advantages over conventional water-soluble dexamethasone compositions owing to its lipid content.
- the present invention is based on the new finding that fat emulsions containing dexamethasone palmitate as the active ingredient are useful in the treatment of ocular inflammations.
- the present invention relates to a pharmaceutical composition in the form of an oil-in-water emulsion for the treatment of ocular inflammations, comprising, as an active ingredient, an effective amount of a lipophilic ester of dexamethasone, e.g. dexamethasone palmitate.
- Emulsion is a dispersion of one liquid in a second immiscible liquid. Since the majority of emulsions contain water as one of the phases, it is customary to classify emulsions into two types: the oil-in-water (O/W) type consisting of colloid particles dispersed in water, and the water-in-oil (W/O) type in which the phases are reversed.
- O/W oil-in-water
- W/O water-in-oil
- the continuous liquid is referred as the dispersion medium and the liquid which is in the form of particles is called the disperse phase.
- each colloid particle has an oily core and an external layer comprising the emulsifiers and the surface active substances.
- a commercially available fat emulsion which contains 10% soybean oil is Intralipid® (Pharmacia AB, Sweden).
- Oil-in-water type emulsions which thus comprise oil-based particles dispersed in an aqueous medium, are capable of incorporating into their oily core or into their interfacial film, various hydrophobic drugs, and accordingly have been proposed and used as pharmaceutical carriers of such drugs.
- the present invention relates to such an oil-in-water type emulsion comprising a lipophilic ester of dexamethasone, as the pharmaceutical active ingredient (namely the drug), for the treatment of ocular inflammations.
- the emulsion typically comprises, in addition to the active ingredient, an oil component and another component, being an emulsifier and/or a surface active agent.
- the aqueous phase typically comprises an osmotic pressure regulating agent dissolved therein, for raising the osmotic pressure to physiological levels.
- concentrations of the ingredients of the emulsion will be given as %, meaning weight of ingredient in hundred volume units of total composition (w/v).
- the composition of the invention comprises an effective amount of a lipophilic ester of dexamethasone.
- the term "effective amount” should be understood as an amount sufficient to impart a therapeutic effect.
- the effective amount in the composition depends on the dosage form, on the therapeutic regime (namely whether the composition is given once daily, twice daily, etc.), the age group of the patient, the severity of the inflammation, as well as on various other factors as known per se. The artisan will have no difficulties in determining, by routine and straight-forward experimentation, as to what constitutes an effective amount in each case.
- Typical examples of lipophilic esters of dexamethasone are esters of dexamethasone with fatty acids, typically such acids having chains of 6 to about 22 carbon atoms.
- fatty acid particularly examples are palmitic acid, oleic acid, linoleic acid, stearic acid and others.
- a particularly preferred fatty acid is palmitic acid (namely the active agent is preferably dexamethasone palmitate).
- Dexamethasone palmitate may typically be included in the composition ranging between 0.05%, typically 0.1% and preferably 0.15% to 0.5%, typically 0.4% and preferably 0.3%.
- the oil component is typically a vegetable oil.
- vegetable oils are oleic acid, linoleic acid, lauric acid, soybean oil, olive oil, sunflower oil, and others.
- Vegetable oil is typically included in a concentration range of about 5% to 30% (w/v).
- Typical emulsifiers are phospholipids.
- phospholipids are phosphatidylcholin, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine and sphingomyelins.
- Phospholipids are preferably included in a concentration range of about 0.5%- 10% (w/v), and particularly in a concentration range of 1-5%.
- Typical examples of surfactants are polyalkylene glycols having an average molecular weight of 1,000 to 10,000, polyoxyalkylene copolymers having an average molecular weight of 1,000 to 10,000 and poly- oxyethylene fatty acid esters.
- osmotic pressure regulators examples include sucrose or glycerine.
- compositions of the inventions may comprise various preservation agents such as methyl, ethyl and butyl paraben, or antioxidants such as ⁇ -tocopherol and ascorbic acid.
- the pharmaceutical composition of the invention is typically provided in a suitable dosage form, e.g. in the form of eye drops, with the concentration of the active ingredient being such so that a given amount of drops, e.g. 1-2 to be administered at each time.
- the present invention also provides a method of treatment of ocular inflammations comprising topically applying to the eye an oil-in-water type emulsion, comprising a lipophilic ester of dexamethasone as the active ingredient. Still further provided by the invention is use of a lipophilic ester of dexamethasone and an oil-in-water type emulsion, for the preparation of a topical ocular composition for the treatment of ocular inflammations.
- Figs. 1-3 are bar graphs (means ⁇ SD) showing the overall score of clinical examination (Fig. 1), the aqueous humor protein content (Fig. 2) and the aqueous humor cell count (Fig. 3) in a variety of treatments: control (A,B), treatment with a reference composition (C,D) and treatment with the inventive composition (E,F).
- control A,B
- C,D treatment with a reference composition
- inventive composition E,F
- the left eye was injected with LPS (results are shown as columns A, C and E in each of Figs. 1-3) and the right eye was injected with saline (results shown as columns B, D and F in each of Figs. 1-3).
- the albino rabbit has been selected for this study, since it is widely acclaimed in reports published in the scientific literature, as a most suitable experimental model for the evaluation of newly developed and clinically applied agents for the therapy of anterior uveitis.
- Rabbits were kept within a limited access laboratory animal facility, at environmental conditions of a target temperature of 17 to 23 °C, a target humidity of 30-70% and a 12-hour light/12-hour dark cycle. Temperature and relative humidity were recorded daily. No deviation from the target values were observed. Rabbits were housed individually in stainless steel cages, mounted in batteries. The cages measured 50x45x48 cm and were fitted with perforated stainless steel floors over undertrays.
- a complete commercial pelleted rabbit diet (AMBAR 19701) was fed without restriction and the animals were allowed free access to water supplied via a cage-side water bottle.
- Test composition a commercially available composition comprising an oil-in-water type emulsion containing dexamethasone palmitate at a concentration of 4 mg/ml (LIMETHASONTM, Green Cross Corporation, Japan).
- Reference composition a commercially available clear aqueous ophthalmic solution, containing 1 mg/ml dexamethasone disodium phosphate (STERODEXTM, Fischer Pharmaceutical Labs. (1975) Ltd., Israel).
- EIU was carried out in all animals of the three test groups by endotoxin lipopolysaccharide ( PS-E.coli), injected intravitreally at a dose of 2 ⁇ g (40 ⁇ l of 50 ⁇ l LPS/1 ml HPCD [hydroxypropyl cyclodextrin]) into the left eye of each test animal. Throughout the procedure, animals were anesthetized by intramuscular injection of Ketamin HCL 30 mg/kg and Xylazine HCL 5 mg/kg.
- EIU Control Contralateral (right) eyes served as controls for LPS-injected eyes, and were injected intravitreally in an identical fashion, using 50 ⁇ l of sterile saline.
- tertiary vessels are considered to be substantially hyperemic.
- 2 Minimal injection of tertiary vessels and minimal to moderate injection of secondary vessels or iris stroma swelling alone.
- 3 Moderate injection of secondary and tertiary vessels. .
- slight swelling of iris stroma (most prominent near the 3:00 and 9:00 o'clock positions).
- 4 Marked injection of the secondary and tertiary vessels with marked swelling of the iris stroma. Iris appears rugose and may be accompanied by hemorrhage in the anterior chamber.
- mice were anesthetized (Ketamin HCL 100 mg/kg and Xylazine HCL 15 mg/kg by i.m. injection) and aqueous humor was sampled from both eyes of each test animal, using an appropriate hypodermic needle and syringe. Differential cell counts were determined using a hemocytometer.
- Table 1 summarizes the data for all test groups, with respect to the evaluation criteria of clinical grading, aqueous humor protein content and cell count, for each of the three types of treatments.
- FIGs. 1-3 show the same results presented in Table 1 in a more illustrative graphic form: Fig. 1 - overall criterion of clinical examination;
- Fig. 2 aqueous humor protein content
- Fig. 3 aqueous humor cell count.
- A, B - untreated control A - LPS-injected left eye and B - saline-injected right eye.
- C,D - animals treated with the reference composition C - LPS-injected left eye, D - saline-injected right eye.
- E.F - animals treated with the test composition E - LPS-injected left eye, F - saline-injected right eye.
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Ophthalmology & Optometry (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000508372A JP2001514228A (ja) | 1997-08-28 | 1998-08-26 | パルミチン酸デキサメタゾンを含有する眼炎症を治療するための薬学的組成物 |
AU88839/98A AU8883998A (en) | 1997-08-28 | 1998-08-26 | Pharmaceutical compositions for the treatment of ocular inflammations comprisingdexamethasone palmitate |
CA002300850A CA2300850A1 (en) | 1997-08-28 | 1998-08-26 | Pharmaceutical compositions for the treatment of ocular inflammations comprising dexamethasone palmitate |
EP98940536A EP1009409A1 (en) | 1997-08-28 | 1998-08-26 | Pharmaceutical compositions for the treatment of ocular inflammations comprising dexamethasone palmitate |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IL12164797A IL121647A (en) | 1997-08-28 | 1997-08-28 | Pharmaceutical compositions for the treatment of ocular inflammation comprising dexamethasone palmitate |
IL121647 | 1997-08-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999011270A1 true WO1999011270A1 (en) | 1999-03-11 |
Family
ID=11070569
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IL1998/000411 WO1999011270A1 (en) | 1997-08-28 | 1998-08-26 | Pharmaceutical compositions for the treatment of ocular inflammations comprising dexamethasone palmitate |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP1009409A1 (zh) |
JP (1) | JP2001514228A (zh) |
CN (1) | CN1271288A (zh) |
AU (1) | AU8883998A (zh) |
CA (1) | CA2300850A1 (zh) |
IL (1) | IL121647A (zh) |
WO (1) | WO1999011270A1 (zh) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007138113A1 (en) * | 2006-06-01 | 2007-12-06 | Novagali Pharma Sa | Use of a steroid prodrug for the treatment of disease of the posterior segment of the eye |
WO2009071594A1 (en) * | 2007-12-04 | 2009-06-11 | Novagali Pharma Sa | Compositions comprising corticosteroid prodrug such as dexamethasone palmitate for the treatment of eye disorders |
KR101541416B1 (ko) | 2006-06-01 | 2015-08-03 | 산텐 에스에이에스 | 후안부 질환 치료를 위한 스테로이드 전구약물의 용도 |
US20180303869A1 (en) * | 2006-03-14 | 2018-10-25 | Clarus Cls Holdings, Llc | Methods of using ophthalmic compositions comprising povidone-iodine |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BR0312635A (pt) * | 2002-07-15 | 2005-04-19 | Alcon Inc | Composições de implante farmacêutico lipofìlico não polimérico para uso intraocular |
CN108434090A (zh) * | 2017-02-14 | 2018-08-24 | 高药品股份有限公司 | 以生理脂肪为基剂的类固醇药膏 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0041772A2 (en) * | 1980-05-15 | 1981-12-16 | Green Cross Corporation | Fat emulsion containing a steroid |
EP0253472A1 (en) * | 1986-05-16 | 1988-01-20 | Green Cross Corporation | Ophthalmic flurbiprofen preparation |
EP0315079A1 (en) * | 1987-10-28 | 1989-05-10 | Nippon Shinyaku Company, Limited | Drug carriers |
JPH05124965A (ja) * | 1991-11-06 | 1993-05-21 | L T T Kenkyusho:Kk | 局所用鼻・気管支疾患治療剤 |
-
1997
- 1997-08-28 IL IL12164797A patent/IL121647A/en not_active IP Right Cessation
-
1998
- 1998-08-26 JP JP2000508372A patent/JP2001514228A/ja active Pending
- 1998-08-26 WO PCT/IL1998/000411 patent/WO1999011270A1/en not_active Application Discontinuation
- 1998-08-26 CN CN98809486A patent/CN1271288A/zh active Pending
- 1998-08-26 EP EP98940536A patent/EP1009409A1/en not_active Ceased
- 1998-08-26 AU AU88839/98A patent/AU8883998A/en not_active Abandoned
- 1998-08-26 CA CA002300850A patent/CA2300850A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0041772A2 (en) * | 1980-05-15 | 1981-12-16 | Green Cross Corporation | Fat emulsion containing a steroid |
US4340594A (en) * | 1980-05-15 | 1982-07-20 | The Green Cross Corporation | Fat emulsion containing steroid |
EP0253472A1 (en) * | 1986-05-16 | 1988-01-20 | Green Cross Corporation | Ophthalmic flurbiprofen preparation |
EP0315079A1 (en) * | 1987-10-28 | 1989-05-10 | Nippon Shinyaku Company, Limited | Drug carriers |
JPH05124965A (ja) * | 1991-11-06 | 1993-05-21 | L T T Kenkyusho:Kk | 局所用鼻・気管支疾患治療剤 |
Non-Patent Citations (2)
Title |
---|
PATENT ABSTRACTS OF JAPAN vol. 17, no. 489 (C - 1106) 6 September 1993 (1993-09-06) * |
TANIGUCHI ET AL.: "Efficacy of a liposome preparation of anti-inflammatory steroid as an ocular drug-delivery system", J. PHARMACOBIO-DYN., vol. 11, no. 1, 1988, pages 39 - 46, XP002084887 * |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20180303869A1 (en) * | 2006-03-14 | 2018-10-25 | Clarus Cls Holdings, Llc | Methods of using ophthalmic compositions comprising povidone-iodine |
US10849928B2 (en) * | 2006-03-14 | 2020-12-01 | Clarus Cls Holdings, Llc | Methods of using ophthalmic compositions comprising povidone-iodine |
US9192567B2 (en) | 2006-06-01 | 2015-11-24 | Santen Sas | Method for treating eye disease or conditions affecting the posterior segment of the eye |
WO2007138113A1 (en) * | 2006-06-01 | 2007-12-06 | Novagali Pharma Sa | Use of a steroid prodrug for the treatment of disease of the posterior segment of the eye |
WO2007138114A1 (en) * | 2006-06-01 | 2007-12-06 | Novagali Pharma Sa | Use of prodrugs for ocular intravireous administration |
EP1864668A1 (en) * | 2006-06-01 | 2007-12-12 | Novagali Pharma SA | Use of prodrugs for ocular intravitreous administration |
EP2319517A1 (en) * | 2006-06-01 | 2011-05-11 | Novagali Pharma S.A. | Use of prodrugs for ocular intravitreous administration |
EP2322183A1 (en) * | 2006-06-01 | 2011-05-18 | Novagali Pharma S.A. | Use of prodrugs for ocular intravitreous administration |
US8227452B2 (en) * | 2006-06-01 | 2012-07-24 | Novagali Pharma Sa | Use of a steroid prodrug for the treatment of disease of the posterior segment of the eye |
CN101553235B (zh) * | 2006-06-01 | 2012-12-05 | 诺瓦加利制药公司 | 甾族化合物前药在治疗眼后段疾病中的用途 |
AU2007267079B2 (en) * | 2006-06-01 | 2013-01-31 | Santen Sas | Use of a steroid prodrug for the treatment of disease of the posterior segment of the eye |
EP1864667A1 (en) * | 2006-06-01 | 2007-12-12 | Novagali Pharma SA | Use of prodrugs for ocular intravitreous administration |
KR101541416B1 (ko) | 2006-06-01 | 2015-08-03 | 산텐 에스에이에스 | 후안부 질환 치료를 위한 스테로이드 전구약물의 용도 |
KR101408317B1 (ko) * | 2006-06-01 | 2014-06-17 | 산텐 에스에이에스 | 후안부 질환 치료를 위한 스테로이드 전구약물의 용도 |
US8623852B2 (en) | 2007-12-04 | 2014-01-07 | Santen Sas | Topical methods and compositions for the treatment of eye diseases and conditions |
EP2564853A1 (en) * | 2007-12-04 | 2013-03-06 | Novagali Pharma S.A. | Compositions comprising corticosteroid prodrug such as dexamethasone palmitate for the treatment of eye disorders |
KR101805116B1 (ko) | 2007-12-04 | 2017-12-06 | 산텐 에스에이에스 | 덱사메타손 팔미테이트와 같은 코르티코스테로이드 전구약물을 포함하는 안과질환 치료용 조성물 |
KR101805852B1 (ko) | 2007-12-04 | 2018-01-10 | 산텐 에스에이에스 | 덱사메타손 팔미테이트와 같은 코르티코스테로이드 전구약물을 포함하는 안과질환 치료용 조성물 |
US20100286065A1 (en) * | 2007-12-04 | 2010-11-11 | Novagali Pharma Sa | Topical methods and compositions for the treatment of eye diseases and conditions |
WO2009071594A1 (en) * | 2007-12-04 | 2009-06-11 | Novagali Pharma Sa | Compositions comprising corticosteroid prodrug such as dexamethasone palmitate for the treatment of eye disorders |
Also Published As
Publication number | Publication date |
---|---|
JP2001514228A (ja) | 2001-09-11 |
IL121647A (en) | 2001-07-24 |
CN1271288A (zh) | 2000-10-25 |
CA2300850A1 (en) | 1999-03-11 |
EP1009409A1 (en) | 2000-06-21 |
IL121647A0 (en) | 1998-02-08 |
AU8883998A (en) | 1999-03-22 |
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