WO1995000144A1 - Composition for ophthalmic use - Google Patents
Composition for ophthalmic use Download PDFInfo
- Publication number
- WO1995000144A1 WO1995000144A1 PCT/FI1994/000270 FI9400270W WO9500144A1 WO 1995000144 A1 WO1995000144 A1 WO 1995000144A1 FI 9400270 W FI9400270 W FI 9400270W WO 9500144 A1 WO9500144 A1 WO 9500144A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition according
- cyclodextrin
- composition
- eye
- buffers
- Prior art date
Links
- 0 C[C@@](C(Cc1cnc[n]1C)CO*)C(C)=O Chemical compound C[C@@](C(Cc1cnc[n]1C)CO*)C(C)=O 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- 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
Definitions
- the present invention relates to a composition for the topical treatment of the eye, which as the active ingre ⁇ transducer contains a pilocarpine derivative, specifically a bispilocarpic acid diester.
- the object of the invention is to eliminate or at least reduce some of the disadvantages associated with the administration of pilocarpine.
- Pilocarpine is a drug which is used for the treatment of glaucoma, which drug lowers the ocular pressure by increasing the flow of chamber fluid from the eye.
- the intraocular pressure reducing effect of pilocarpine is based on the ciliary muscle contracting effect of the drug, by widening the angle of the anterior chamber which is important from the viewpoint of the outflow of the chamber fluid and the outflow of the fluid is facilitated.
- Pilocarpine is absorbed into the eye through the cornea. In the cornea it is first absorbed in the dense epithelium layer on the eye surface containing cell membrane lipids (fats) in abundance. However, pilocarpine is not very lipid soluble, wherefore it penetrates relatively little into the corneal epithelium, which delivers pilocarpine through the aqueous stroma and endotheliu of the cornea into the fluid of the anterior chamber. From the chamber fluid, pilocar ⁇ pine has easy access to its action site, the ciliary muscle.
- pilocarpine In order to improve and prolong the action of the drug, pilocarpine must be used in relatively big doses. From this follows that shortly after administration, peak pilocarpine levels are obtained in the chamber, fluid, in the iris and the ciliary muscle which lead to a strong contraction of the pupil (miosis) and accommodation of the eye to seeing at close distance. Pilocarpine, however, leaves the eye rapidly and is therefore administered 3 to 8 times daily, depending on the patient. Each administration is followed by the aforementioned disadvantages.
- pilocarpine prodrugs i.e. bispilocarpic acid diesters (WO 92/09583) .
- These derivatives are more lipid soluble than pilocarpine and thus provide an improved absorption. They degrade through enzymatic and chemical hydrolysis in the corneal epithelium to liberate the pharmaceutically effec- tive pilocarpine and the ineffective pro-moiety.
- the pro-moiety is superfluous in view of the pharmaceutical effect, it is important that the eye is subjected to as small amounts of pro-moiety as possible. Thus it is of importance also for this reason to lower the amount of drug administered to the eye.
- the bispilocarpic acid diesters (BD) being very lipid soluble compounds, readily enter the fatty film of the corneal epithelium, wherefore it is of importance to be able to control the rate of absorption of drug into the corneal epithelium and to avoid peak concentrations, which cause i.a. eye irritation.
- Cyclodextrins are cyclic oligosaccharides having the general formula
- the free hydroxy group(s) may be etherified, for example with alkyl or hydroxyalkyl groups, or esterified. Also branched or polymeric cyclodextrins may come into question.
- the cyclodextrins are known to form adducts and inclusion complexes with a number of compounds and it is also known to administer drugs complexed with cyclodextrins in order to improve for example the solubility and the stability of the drug. Increased solubility and stability in cyclodex- trin complexes is related to the hydrophobicity of the inner cyclodextrin cavity.
- the aim of the present invention is to provide a composi- tion for ophthalmological use in the form of an aqueous solution of a bispilocarpic acid diester, which provides for an increase in the total amount of drug delivered to the eye, for a prolonged duration thereof, while simul ⁇ taneously reducing its peak concentration and associated side effects, such as eye irritation.
- the composition By means of the composition the number of daily administration times may be reduced, which leads to improved patient compliance.
- the object of the invention is thus a composition for the topical administration of bispilocarpic acid diester to the eye in the form of an aqueous solution, which is charac ⁇ terized in that it includes cyclodextrin.
- the cyclodextrin molecules form complexes with some of the prodrug molecules in the composition, while some remain free in the solution.
- the cyclodextrin is included in an amount of 1 - 40 % (weight/volume) .
- any pharmaceutically accep ⁇ table cyclodextrin derivative may be used.
- the cyclodextrin may also be substituted in one or more of the 2-, 3- and/or 6-positions.
- they are cyclodextrin ethers, preferably lower alkyl or lower hydroxyalkyl, e.g. methyl, ethyl, hydroxyethyl, hydroxypropyl, e.g. 2-hydroxypropyl derivatives and esters such as acylates, sulfonates, sulfates and phosphates, or mixed derivatives.
- Increased water solubility and benefi ⁇ cial viscosity and mucoadhesive properties can also be gained by exploiting suitable branched cyclodextrins, such as their gluco ⁇ yl and altosyl derivatives, or linear covalently bonded oligomers and other linked or polymeric cyclodextrins, or their combinations.
- suitable branched cyclodextrins such as their gluco ⁇ yl and altosyl derivatives, or linear covalently bonded oligomers and other linked or polymeric cyclodextrins, or their combinations.
- deriva ⁇ tives with hydroxy-substituted side chain have a better solubility, viscosity and adhesion characteristics, where desired.
- cyclodextrin is a /3-cyclodextrin, preferably a jS-cyclodextrin alkylated and/or hydroxyalkylated in the 2-,3- and/or 6-position.
- the composition may, in addition, contain a viscosity enhancing agent and the viscosity is adjusted to the desired level with a substance suitable for the purpose.
- a viscosity enhancing agent such as hydroxypropyl- methylcellulose, sodium carboxymethylcellulose, methylcel- lulose, polyvinylpyrrolidone, polyvinylalcohols, dextrans, polyacrylic acids, chitosan ⁇ , hyaluronic acid etc.
- the amount of polymer to be added depends on the desired viscosity level, and on the polymer used, and can be easily determined by a person skilled in the art.
- the viscosity enhancing agent is thus used in an amount to provide a suitable thickness to the composition, which usually means a viscosity of 1 - 25000 mPas.
- the viscosity is measured with a Brookfield viscosimeter (type LVDV-III) at a the temperature of 22 °C and a shear rate (D) of 1 s 1 for viscosities of 100 - 25000 mPas, and a shear rate of 60 s" 1 for viscosities of 1 - 100 mPas.
- the viscosity enhancing agent provides for a longer contact time of the composition with the eye surface, the total amount of the drug absorbed thus being increased as well as providing for a prolonged action.
- the viscosity enhancing agent also slows down the neutralization rate of the acidic or slightly acidic composition on the eye surface, which in turn affects the uptake of prodrug, as the fat solubility of the BD's is all the more pronounced, the more neutral the solution is.
- the uptake of prodrug may thus be controlled to some extent also in this manner.
- compositions according to the invention may also include further adjuvants, for example preservatives, such as quaternary ammonium compounds, e.g. benzalkonium chlori ⁇ de, benzyl alcohol, mercury salts, thiomersal, chlor- hexidine, chlorobutanol or the like.
- preservatives such as quaternary ammonium compounds, e.g. benzalkonium chlori ⁇ de, benzyl alcohol, mercury salts, thiomersal, chlor- hexidine, chlorobutanol or the like.
- the composition may in addition contain a buffer.
- buffering systems may be mentioned phosphate buffers, borate buffers, acetate buffers and citrate buffers, or mixed buffers.
- the buffers are usually used, depending on the desired pH and buffering capacity desired, in concentrations of 5 to 100 M.
- concentrations of 5 to 100 M The choice of amount and kind of buffer lies within the knowledge of the person skilled in the art.
- the buffer may regulate the equi ⁇ librium of complexed and free prodrug.
- the pH of the composition is preferably 3 - 8, advan- tageously approximately 5 - 7.
- composition according to the invention is preferably used in the form of an isotonic solution (corresponding to a 0.9 % NaCl-solution) and the tonicity may be varied by using substances conventionally used for this purpose, such as sodium chloride, potassium chloride, glycerol, mannitol, sorbitol, xylitol, sodium borate, sodium acetate and the like.
- the bispilocarpic acid diesters are preferably those compounds which are disclosed in the WO-publications 92/- 09583 and 93/24466, the contents of which are included here for reference.
- Y is hydrogen or -C-R, wherein R is hydrogen, 0,-0 ⁇ - alkyl, C 2 -C 18 -alkenyl, C 2 -C 18 -alkynyl, optionally substituted C 3 -C 7 -cycloalkyl or C 3 -C 7 -cycloalkenyl, optionally substitu- ted aryl or aryl lower alkyl, and W is the group
- Y' has the meaning of hydrogen or the group -C-R", wherein R* has the meaning of R above, whereby R' can be the same as or different from R
- A is optionally hydroxy or protected-hydroxy substituted C j -C ⁇ -alkylene, C 2 -C lg - alkenylene, C 2 -C 18 -alkynylene, which may be substituted by optionally substituted C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkenyl, aryl, or aryl lower alkyl, or A is optionally substituted C 3 -C 7 -cycloalkylene or C 3 -C 7 -cycloalkenylene or arylene, or A is the aforementioned alkylene, alkenylene, or alkynyle- ne, which as a chain member contains the afore defined cycloalkylene, cycloalkenylene or arylene group, and -Z-
- W is -OR, wherein R has the meaning given above, Y is 0 0 -C 11-B-C ⁇ -Z'-OR' , wherein R' has the meaning given above and
- Preferred compounds are e.g. the diacyl bispilocarpates according to formula IA) , wherein acyl is lower alkyl(1- 4C)-, lower cycloalkyl(3-6C)-carbonyl or benzoyl, A is lower alkylene(2-6C) , lower cycloalkylene(3-6C) or arylene, specifically 0,0*-diacetyl-, O,0'-dipropionyl-, 0,0'- dibutyryl-, 0,0'-valeryl- and 0,O'-dicyclopropylcarbonyl (1,4-, 1,3-, 1,2-xylylene)- and -(1,2-ethylene)-, -(1,3- propylene)-, -(1,4-butylene)-, -(1,5-pentylene)- and -(1,6- hexylene) bispilocarpate, especially -(1,4-xylylene) bispilo
- A is ethylene, or A is 1,3-propylene, which can be substituted in its 2-position with hydroxy, the group Y-O- wherein Y has the meaning given, or with one or two methyl groups.
- a subgroup of the compounds of the formula IB) is formed by the compounds, wherein W is OR', wherein R 1 has the meaning of C 1 -C 4 -alkyl or C 3 -C 6 -cycloalkyl, and B is 1,2-ethylene, 1,3-propylene or 1,4-butylene.
- Another preferred group of compounds of the formula IB) is comprised of e.g. the (dibenzyl) and (dilower alkyl) bis- pilocarpates, such as 0,0'-glutaryl-, 0,0'-disuccinyl-, O,0'-adipoyl (dibenzyl)- and -(dilower alkyl) bispilocar ⁇ pate.
- the (dibenzyl) and (dilower alkyl) bis- pilocarpates such as 0,0'-glutaryl-, 0,0'-disuccinyl-, O,0'-adipoyl (dibenzyl)- and -(dilower alkyl) bispilocar ⁇ pate.
- the concentration of the BD's in the composition according to the invention may vary, but is suitably from 0.05 - 4, preferably 0.5 - 2 weight %, calculated as the pilocarpine base.
- the concentration of cyclodextrin is preferably 5 - 20 % by weight.
- the amount of active ingredient refers to the pilocarpine base.
- composition according to the invention was made having the following ingredients:
- The. concentration of active ingredient is 1.0 % and it contains 5% (w/v) of cyclodextrin.
- the pH of the solution is 5.
- composition according to the invention was made having the following ingredients:
- the concentration of active ingredient is 1.0 % and that of cyclodextrin is 10 % (w/v) .
- the pH of the solution is 5.
- composition according to the invention was made having the following ingredients:
- the concentration of active ingredient is 1.0 % and that of cyclodextrin is 15 % (w/v) .
- the pH of the solution is 5.
- Example 4 A composition according to the invention was made having the following ingredients:
- the concentration of active ingredient is 0.5 % and that of cyclodextrin is 5 % (w/v) .
- the viscosity is 50 cps and the pH of the solution is 5.
- Example 5 A composition according to the invention was made having the following ingredients:
- the concentration of active ingredient is 0.25 % and that of the cyclodextrin 5 % (w/v).
- Example 6 A composition according to the invention was made having the following ingredients:
- the concentration of active ingredient is 0.5 % and that of the cyclodextrin 7.5 % (w/v) .
- the pH of the solution is 5.
- composition according to the invention was made having the following ingredients:
- the concentration of active ingredient is 1.0 % and that of the cyclodextrin 15 % (w/v) .
- the pH of the solution is 5.
- composition according to the invention was made having the following ingredients: 0,0'-Dicyclopropylcarbonyl (1,6-hexylene) bispilocarpate
- the concentration of active ingredient is 0.5 % and that of the cyclodextrin is 10 % (w/v) .
- the pH of the solution is 5.
- composition according to the invention was made having the following ingredients:
- the concentration of active ingredient is 1.0 % and that of the cyclodextrin is 20 % (w/v) .
- the pH of the solution is 5.
- compositions according to the invention were compared on the one hand to a commercial pilocarpine formulation (Oftan Pilocarpine 2%; reference composition 1) and on the other hand to compositions of the same prodrug in an aqueous solution without cyclodextrin (reference compositions 2-5) in the same tests and under the same conditions.
- Reference compositions 2-5 compositions of the same prodrug in an aqueous solution without cyclodextrin
- AUC area under curve; relates to the amount of drug absorbed
- Maximum miosis maximum contraction of the pupil in percentages, compared to time 0
- composition Cone of min Max. nk)sls>3% irritation 3 solution (% min) miosis (%) (min) (min) eye closed eye half-
- Example 2 1.0 2318 ⁇ 396 13+1 103 ⁇ 24 276 ⁇ 32 + +++ i
- Example 3 1.0 3008 ⁇ 584 14 ⁇ 2 132 ⁇ 44 279 ⁇ 45 - +
- the compounds are absorbed from an agueous cyclodextrin containing solution into the cornea and release pilocarpine in a controlled manner causing miosis.
- the amount of prodrug absorbed from a cyclodextrin solution is dependent on the complexation constant of the prodrug with the cyclodextrin molecule.
- the complexation constant in turn is affected by the physico-chemical properties of prodrug and cyclodextrin.
- concentration ratio of prodrug and cyclodextrin in the solution affects the fractions of complexed and free prodrug.
- a composition containing 1 % prodrug in a cyclodextrin solution gives substantially longer miosis as compared to the reference composition 1 (Examples 2 and 3: 1.8 times longer) and also as compared to the reference composition 2 (Examples 2 and 3: 1.5 times longer).
- the lower maximum miosis shows that the compositions of the invention are able to reduce the peak concentration of pilocarpine, thus reducing the side effects in the eye.
- Maximum miosis of the compositions of the invention is reached three times as late as compared to the reference composition 1. The maximum miosis is also reached later (1.5 times as late) from a composition containing cyclodex- trin than when administering the prodrug from an aqueous solution without cyclodextrin (reference composition 2) . This demonstrates the slower rate of prodrug absorption from a cyclodextrin complex.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nanotechnology (AREA)
- Medical Informatics (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Biophysics (AREA)
- Inorganic Chemistry (AREA)
- Ophthalmology & Optometry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU69731/94A AU6973194A (en) | 1993-06-24 | 1994-06-17 | Composition for ophthalmic use |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9302203A SE501482C2 (sv) | 1993-06-24 | 1993-06-24 | Komposition för topisk administration av bispilokarpinsyradiestrar till ögat i form av en vattenlösning |
SE9302203-6 | 1993-06-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995000144A1 true WO1995000144A1 (en) | 1995-01-05 |
Family
ID=20390417
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FI1994/000270 WO1995000144A1 (en) | 1993-06-24 | 1994-06-17 | Composition for ophthalmic use |
Country Status (5)
Country | Link |
---|---|
AU (1) | AU6973194A (sv) |
EE (1) | EE9400040A (sv) |
LT (1) | LT3525B (sv) |
SE (1) | SE501482C2 (sv) |
WO (1) | WO1995000144A1 (sv) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0777415A1 (en) * | 1994-07-11 | 1997-06-11 | David W. Pate | Anandamide analogue compositions and method of treating intraocular hypertention using same |
WO1998055148A1 (en) * | 1997-06-05 | 1998-12-10 | Janssen Pharmaceutica N.V. | Pharmaceutical compositions comprising cyclodextrins |
US6933289B2 (en) | 2003-07-01 | 2005-08-23 | Allergan, Inc. | Inhibition of irritating side effects associated with use of a topical ophthalmic medication |
US7862552B2 (en) | 2005-05-09 | 2011-01-04 | Boston Scientific Scimed, Inc. | Medical devices for treating urological and uterine conditions |
WO2023225113A1 (en) * | 2022-05-18 | 2023-11-23 | Bexson Biomedical, Inc. | Complexing agent salt formulations of pharmaceutical compounds at low stoichiometric ratios |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0082921A1 (en) * | 1981-12-24 | 1983-07-06 | Kaken Pharmaceutical Co., Ltd. | Anti-inflammatory ophthalmic solution and process for preparing the same |
EP0472327A1 (en) * | 1990-08-13 | 1992-02-26 | Senju Pharmaceutical Co., Ltd. | Composition for eye drops |
WO1992009583A1 (en) * | 1990-11-30 | 1992-06-11 | Leiras Oy | Novel pilocarpine derivatives and process for their preparation |
-
1993
- 1993-06-24 SE SE9302203A patent/SE501482C2/sv unknown
-
1994
- 1994-06-17 WO PCT/FI1994/000270 patent/WO1995000144A1/en active Application Filing
- 1994-06-17 AU AU69731/94A patent/AU6973194A/en not_active Abandoned
- 1994-06-23 LT LTIP1970A patent/LT3525B/lt not_active IP Right Cessation
- 1994-08-18 EE EE9400040A patent/EE9400040A/xx unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0082921A1 (en) * | 1981-12-24 | 1983-07-06 | Kaken Pharmaceutical Co., Ltd. | Anti-inflammatory ophthalmic solution and process for preparing the same |
EP0472327A1 (en) * | 1990-08-13 | 1992-02-26 | Senju Pharmaceutical Co., Ltd. | Composition for eye drops |
WO1992009583A1 (en) * | 1990-11-30 | 1992-06-11 | Leiras Oy | Novel pilocarpine derivatives and process for their preparation |
Non-Patent Citations (1)
Title |
---|
INTERNATIONAL JOURNAL OF PHARMACEUTICS, Volume 75, 1991, TOMI JARVINEN et al., "0,0'-(1,4-Xylylene) Bispilocarpic Acid Esters as New Potential Double Prodrugs of Pilocarpine for Improved Ocular Delivery. II. Physicochemical Properties, Stability, Solubility and Enzymatic Hydrolysis", pages 259-269. * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0777415A1 (en) * | 1994-07-11 | 1997-06-11 | David W. Pate | Anandamide analogue compositions and method of treating intraocular hypertention using same |
EP0777415A4 (en) * | 1994-07-11 | 1999-06-16 | David W Pate | COMPOSITIONS CONTAINING AN ANANDAMIDE ANALOG AND METHOD FOR TREATING INCREASED EYE PRESSURE USING IT |
WO1998055148A1 (en) * | 1997-06-05 | 1998-12-10 | Janssen Pharmaceutica N.V. | Pharmaceutical compositions comprising cyclodextrins |
US6933289B2 (en) | 2003-07-01 | 2005-08-23 | Allergan, Inc. | Inhibition of irritating side effects associated with use of a topical ophthalmic medication |
US7862552B2 (en) | 2005-05-09 | 2011-01-04 | Boston Scientific Scimed, Inc. | Medical devices for treating urological and uterine conditions |
WO2023225113A1 (en) * | 2022-05-18 | 2023-11-23 | Bexson Biomedical, Inc. | Complexing agent salt formulations of pharmaceutical compounds at low stoichiometric ratios |
Also Published As
Publication number | Publication date |
---|---|
LTIP1970A (en) | 1995-01-31 |
SE501482C2 (sv) | 1995-02-27 |
LT3525B (en) | 1995-11-27 |
AU6973194A (en) | 1995-01-17 |
SE9302203D0 (sv) | 1993-06-24 |
EE9400040A (et) | 1995-12-15 |
SE9302203L (sv) | 1994-12-25 |
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