WO1994027578A1 - In situ gel for therapeutic use - Google Patents
In situ gel for therapeutic use Download PDFInfo
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- WO1994027578A1 WO1994027578A1 PCT/SE1994/000522 SE9400522W WO9427578A1 WO 1994027578 A1 WO1994027578 A1 WO 1994027578A1 SE 9400522 W SE9400522 W SE 9400522W WO 9427578 A1 WO9427578 A1 WO 9427578A1
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- 238000011065 in-situ storage Methods 0.000 title claims abstract description 5
- 230000001225 therapeutic effect Effects 0.000 title description 4
- 239000000203 mixture Substances 0.000 claims abstract description 30
- 229940079593 drug Drugs 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 19
- 239000000243 solution Substances 0.000 claims abstract description 14
- 238000012377 drug delivery Methods 0.000 claims abstract description 7
- 239000007788 liquid Substances 0.000 claims abstract description 7
- 229920001477 hydrophilic polymer Polymers 0.000 claims abstract description 6
- 230000007704 transition Effects 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 3
- 239000000815 hypotonic solution Substances 0.000 claims abstract 2
- 229920000642 polymer Polymers 0.000 claims description 8
- 239000002245 particle Substances 0.000 claims description 7
- 229920002148 Gellan gum Polymers 0.000 claims description 6
- 239000011159 matrix material Substances 0.000 claims description 6
- 239000012530 fluid Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 150000002632 lipids Chemical class 0.000 claims description 4
- 239000000216 gellan gum Substances 0.000 claims description 3
- 235000010492 gellan gum Nutrition 0.000 claims description 3
- 150000004676 glycans Chemical class 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 229920001282 polysaccharide Polymers 0.000 claims description 3
- 239000005017 polysaccharide Substances 0.000 claims description 3
- 239000003755 preservative agent Substances 0.000 claims description 3
- 239000008139 complexing agent Substances 0.000 claims description 2
- 239000003456 ion exchange resin Substances 0.000 claims description 2
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims 1
- 239000003002 pH adjusting agent Substances 0.000 claims 1
- 239000000499 gel Substances 0.000 description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 4
- 239000008247 solid mixture Substances 0.000 description 3
- 125000000129 anionic group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000000644 isotonic solution Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- 241000179442 Anacharis Species 0.000 description 1
- 108010001478 Bacitracin Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 1
- 241000790234 Sphingomonas elodea Species 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- BGDKAVGWHJFAGW-UHFFFAOYSA-N Tropicamide Chemical compound C=1C=CC=CC=1C(CO)C(=O)N(CC)CC1=CC=NC=C1 BGDKAVGWHJFAGW-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229940124326 anaesthetic agent Drugs 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- REYFJDPCWQRWAA-UHFFFAOYSA-N antazoline Chemical compound N=1CCNC=1CN(C=1C=CC=CC=1)CC1=CC=CC=C1 REYFJDPCWQRWAA-UHFFFAOYSA-N 0.000 description 1
- 229960002469 antazoline Drugs 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001437 anti-cataract Effects 0.000 description 1
- 230000001384 anti-glaucoma Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000842 anti-protozoal effect Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003904 antiprotozoal agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 229940121357 antivirals Drugs 0.000 description 1
- 229960003071 bacitracin Drugs 0.000 description 1
- 229930184125 bacitracin Natural products 0.000 description 1
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000004397 blinking Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 239000000850 decongestant Substances 0.000 description 1
- 229940124581 decongestants Drugs 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- OCUJLLGVOUDECM-UHFFFAOYSA-N dipivefrin Chemical compound CNCC(O)C1=CC=C(OC(=O)C(C)(C)C)C(OC(=O)C(C)(C)C)=C1 OCUJLLGVOUDECM-UHFFFAOYSA-N 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 1
- 229960000582 mepyramine Drugs 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000002637 mydriatic agent Substances 0.000 description 1
- 230000002911 mydriatic effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229940054534 ophthalmic solution Drugs 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229960001416 pilocarpine Drugs 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- -1 tetrahydrazoline Chemical compound 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229960004791 tropicamide Drugs 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
Classifications
-
- 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
-
- 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 is related to the field of slow release drug delivery systems for therapeutic use, especially in the ophthalmic field, and provides an aqueous liquid composition which in contact with a physiological solution forms a gel matrix which has been found to stay for a considerable time in the administration area, for instance the eye, without causing any problems to the patient.
- This gel can be utilized for controlled continuous administration of drug over a prolonged period of time.
- a composition according to the invention can be used in a number of situations, e.g. oral, buccal, nasal and vaginal administration, when a slow release system is advantageous but will in the following be discussed mainly in connection with it's ophthalmological use since the requirements here are especially high.
- a solid implant containing the active drug is manufactured and delivered to the doctor or nurse for application onto the patient's conjunctiva, preferably under one of the eye lids.
- These type of implants often have an outer membrane layer through which the drug is allowed to diffuse. The release rate depends on the membrane structure as well as the internal matrix in which the drug is incorporated.
- compositions which at room temperature and below this value is liquid (non-solid) is instilled into the eye and due to the rise in temperature forms a polymer matrix, for instance a gel.
- a polymer matrix for instance a gel.
- Some systems have been disclosed which are physiologically acceptable and which form a gel in contact with a physiological salt solution, for instance a tear solution. It is readily appreciated that according to this concept potentially very useful systems for drug delivery are provided.
- compositions of the type mentioned above in contrast to the teaching of the prior art are made hypotonic. Gels formed under these conditions have been found to stay considerably longer in the eye compared to gels formed at higher tonicity values, e.g. under isotonic conditions, hence providing a more efficient delivery system.
- the invention is accordingly related to a liquid hypotonic ophthalmic solution comprising a pharmaceutically active drug and at least one hydrophilic polymer of the type which undergoes liquid-gel phase transition gelling in situ in contact with the physiological solution, for instance tear solution or humour solution when used for intraocular administration.
- a method for administration of a drug is provided using a composition as defined in this specification.
- the hydrophilic polymer is functionally defined by the ability of an aqueous solution of the polymer to form a solid polymer structure, for instance a gel, when the ionic strength is raised to physiological values.
- components belonging to this group include polysaccharides and natural as well as synthetic polysaccharide derivatives.
- the preferred component at present is an extracellular anionic heteropolysaccharide produced by the bacterium Pseudo onas elodea, known as gellan gum and marketed as GelriteTM.
- the gel forming component may in more general terms be any component which before administration is a liquid but forms a gel upon contact with a physiological fluid due to exchange of components between said liquid and the physiological fluid.
- Such exchange of components include but is not limited to proteins, such as lysozymes, and ionic components as discussed above.
- concentration of the gel forming component in cases when Gelrite is used is preferably in the range of from 0.1 to 10 % by weight, especially 0.1-2 % by weight.
- the non- solid composition containing the hydrophilic polymer solution is hypotonic. It has been found, however, that the tonicity should not be too low since this causes undesirable side- effects, such as more or less severe initial irritation when the composition is applied.
- the osmolality of the non-solid composition should accordingly be lower than that of an isotonic solution (about 290 mOs/kg) and a selected range according to this invention is from about 25 - 200 mOs/kg, preferably 25-150 mOs/kg and especially 50-150 mOs/kg.
- the at present most prefered composition has a value around 100 mOs/kg.
- the drug component contained in the composition should preferably be present as a dispersive system, either as a suspension of particles or as an emulsion.
- the drug could be incorporated in or associated with carrier substances in the form of particles e.g. polymers (biodegradable, non- biodegradable or polymers which dissolve or degrade upon contact with a physiological fluid) , lipids or ion-exchange resins.
- EP424042 is disclosed a system based on compositions of the Gelrite type in which the drug is present in particles which dissolve due to change in pH when the composition is instilled into the eye.
- the pH and the buffering capacity of the composition being such that the neutralizing action of lachrymal fluid is sufficient for dissolving the solid microparticles.
- the drug component contained in the composition could also be present as a solution. It may be solubilized by surfactants, lipids or by complex-forming agents.
- the active drug to be administered according to the present invention can be chosen among a great number of components, for instance for ophthalmological use.
- examples of such components include
- - antihistaminics and decongestants for instance pyrilamine, tetrahydrazoline, antazoline and analogues thereof,
- - anti-inflammatories such as flubiprofen, diclofenac, acetylsalicylic acid, cortisone, hydrocortisone, dexamethasone, prednisone, indomethacin and analogues thereof
- antibacterial substances such as tetracyclines, penicillin, bacitracin, sulphonamides and analogues thereof,
- cytotoxics for instance 5-fluorouracil
- - antiglaucoma drugs for instance prostaglandins like the omega chain modified derivatives disclosed in EP0364417 (esp. 13, 14-dihydro-17-phenyl-18, 19,20-trinor-PGF2 ⁇ -isopropylester) and timolol, pilocarpine, epinephrine, dipivalylepinephrine, and their analogues.
- prostaglandins like the omega chain modified derivatives disclosed in EP0364417 (esp. 13, 14-dihydro-17-phenyl-18, 19,20-trinor-PGF2 ⁇ -isopropylester) and timolol, pilocarpine, epinephrine, dipivalylepinephrine, and their analogues.
- composition may contain other additives such as polymers, preservatives, nonionic tonicity agents, solubilizers, buffer agents, complexing agents and chelating agents.
- additives such as polymers, preservatives, nonionic tonicity agents, solubilizers, buffer agents, complexing agents and chelating agents.
- the composition also contained a small amount of fluorescent particles. The time these particles were detectable in the instillation area was measured and taken as an indication of the effectiveness of the drug delivery system.
- a glycerol concentration of 3% is close to an isotonic solution and represents a comparison with a prior art system.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Inorganic Chemistry (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Pharmaceutical drug delivery composition, especially for ophthalmological use, comprising: a liquid hypotonic solution of at least one hydrophilic polymer of the type which undergoes liquid-gel phase transition gelling in situ in contact with a physiological solution, and a pharmaceutically active compound, as well as the use thereof for local administration of drugs.
Description
In situ gel for therapeutic use.
The present invention is related to the field of slow release drug delivery systems for therapeutic use, especially in the ophthalmic field, and provides an aqueous liquid composition which in contact with a physiological solution forms a gel matrix which has been found to stay for a considerable time in the administration area, for instance the eye, without causing any problems to the patient. This gel can be utilized for controlled continuous administration of drug over a prolonged period of time.
A composition according to the invention can be used in a number of situations, e.g. oral, buccal, nasal and vaginal administration, when a slow release system is advantageous but will in the following be discussed mainly in connection with it's ophthalmological use since the requirements here are especially high.
There are a number of situations when topical administration of a drug to the eye would be the most efficient form of therapy and various drop solutions have been developed for this purpose. However, natural mechanisms such as tear rates and blinking, which are important for the protection of the eye by removing dust and contaminants from the surface of the eye, make drug delivery difficult.
A fairly large group of patients have considerable problems to instill a solution onto the eye by themself and the need for slow release systems has therefore been recognized for a long time. There are also a number of therapeutic situations where the efficacy of the drug would benefit from a prolonged occular contact time. According to one concept a solid implant containing the active drug is manufactured and delivered to the doctor or nurse for application onto the patient's conjunctiva, preferably under one of the eye lids. These type of implants often have an outer membrane layer through which the drug is allowed to diffuse. The release rate depends on the membrane structure as well as the internal matrix in which the drug is incorporated. According to another
concept a composition which at room temperature and below this value is liquid (non-solid) is instilled into the eye and due to the rise in temperature forms a polymer matrix, for instance a gel. A somewhat similar approach utilizes the fact that certain polymer solutions in contact with salt ions form a gel. Some systems have been disclosed which are physiologically acceptable and which form a gel in contact with a physiological salt solution, for instance a tear solution. It is readily appreciated that according to this concept potentially very useful systems for drug delivery are provided. Laboratoires Merck, Sharp & Dohme-Chibret have in a series of patent applications described the use of components which undergo liquid-gel phase transition under the effect of an increase in the ionic strength, see for instance AU8663189, EP227494, EP424042 and EP437368. In EP227494 it is mentioned that the test substance fluorescein is still persisting 5 hours after instillation when administered in such a composition.
In these publications an extracellular anionic heteropolysaccharide produced by the bacterium Pseudomonas elodea, known by the name of gellan gum and marketed under the brand name Gelrite™, is presented as the most preferred gel formation component. An aqueous solution of the gel-forming components is prepared containing no or only a very small amount of ionic substances together with the drug in a suitable form and optionally a preservative. It is also pointed out that the non-solid composition should preferably be isotonic and a tonicity adjusting substance, for instance annitol, is added.
We have now surprisingly found that considerably improved drug delivery systems are obtained if compositions of the type mentioned above in contrast to the teaching of the prior art are made hypotonic. Gels formed under these conditions have been found to stay considerably longer in the eye compared to gels formed at higher tonicity values, e.g. under isotonic conditions, hence providing a more efficient delivery system.
The invention is accordingly related to a liquid hypotonic ophthalmic solution comprising a pharmaceutically active drug and at least one hydrophilic polymer of the type which undergoes liquid-gel phase transition gelling in situ in
contact with the physiological solution, for instance tear solution or humour solution when used for intraocular administration.
In another aspect of the invention a method for administration of a drug is provided using a composition as defined in this specification.
The hydrophilic polymer is functionally defined by the ability of an aqueous solution of the polymer to form a solid polymer structure, for instance a gel, when the ionic strength is raised to physiological values. Examples of components belonging to this group include polysaccharides and natural as well as synthetic polysaccharide derivatives. The preferred component at present is an extracellular anionic heteropolysaccharide produced by the bacterium Pseudo onas elodea, known as gellan gum and marketed as Gelrite™. The gel forming component may in more general terms be any component which before administration is a liquid but forms a gel upon contact with a physiological fluid due to exchange of components between said liquid and the physiological fluid. Such exchange of components include but is not limited to proteins, such as lysozymes, and ionic components as discussed above. The concentration of the gel forming component in cases when Gelrite is used is preferably in the range of from 0.1 to 10 % by weight, especially 0.1-2 % by weight.
The inventive concept is as mentioned above that the non- solid composition containing the hydrophilic polymer solution is hypotonic. It has been found, however, that the tonicity should not be too low since this causes undesirable side- effects, such as more or less severe initial irritation when the composition is applied.
The osmolality of the non-solid composition should accordingly be lower than that of an isotonic solution (about 290 mOs/kg) and a selected range according to this invention is from about 25 - 200 mOs/kg, preferably 25-150 mOs/kg and especially 50-150 mOs/kg. The at present most prefered composition has a value around 100 mOs/kg.
The drug component contained in the composition should preferably be present as a dispersive system, either as a
suspension of particles or as an emulsion. The drug could be incorporated in or associated with carrier substances in the form of particles e.g. polymers (biodegradable, non- biodegradable or polymers which dissolve or degrade upon contact with a physiological fluid) , lipids or ion-exchange resins.
In EP424042 is disclosed a system based on compositions of the Gelrite type in which the drug is present in particles which dissolve due to change in pH when the composition is instilled into the eye. The pH and the buffering capacity of the composition being such that the neutralizing action of lachrymal fluid is sufficient for dissolving the solid microparticles.
Examples of methods for producing lipid particles containing an ophthalmologically active substance are given in EP 437368.
The drug component contained in the composition could also be present as a solution. It may be solubilized by surfactants, lipids or by complex-forming agents.
The active drug to be administered according to the present invention can be chosen among a great number of components, for instance for ophthalmological use. Examples of such components include
- antihistaminics and decongestants, for instance pyrilamine, tetrahydrazoline, antazoline and analogues thereof,
- anti-inflammatories such as flubiprofen, diclofenac, acetylsalicylic acid, cortisone, hydrocortisone, dexamethasone, prednisone, indomethacin and analogues thereof
- antiparasitc and/or antiprotozoal compounds
- antibacterial substances such as tetracyclines, penicillin, bacitracin, sulphonamides and analogues thereof,
- mydriatics, for instance cyclopentanol and tropicamide
- cytotoxics, for instance 5-fluorouracil
- antiglaucoma drugs, for instance prostaglandins like the omega chain modified derivatives disclosed in EP0364417 (esp. 13, 14-dihydro-17-phenyl-18, 19,20-trinor-PGF2α-isopropylester) and timolol, pilocarpine, epinephrine, dipivalylepinephrine, and their analogues.
- antivirals
- antioxidants
- anticataracts
- antiallergics
- anaesthetics
The composition may contain other additives such as polymers, preservatives, nonionic tonicity agents, solubilizers, buffer agents, complexing agents and chelating agents.
Examples.
The relevance of the concept was verified in a series of experiments in which compositions comprising
Gelrite (various concentrations)
Benzalkonium chloride 0.01 g and Glycerol (0 - 3%), for adjusting the tonicity, in 100 ml of ultrapure water
were instilled into one of the eyes of a healthy volounteer. For measuring the duration time, or contact time, the composition also contained a small amount of fluorescent particles. The time these particles were detectable in the instillation area was measured and taken as an indication of the effectiveness of the drug delivery system.
A glycerol concentration of 3% is close to an isotonic solution and represents a comparison with a prior art system.
It should be noticed that with no addition of the tonicity adjusting component, glycerol, initial pain for half a minute or even more was reported by the test persons. A composition for use in the eye should for this reason have an osmolatity value of at least 25 mOs/kg.
From the results presented above it can be concluded that considerably longer contact times have now been achieved compared to the results indicated in the prior art literature.
Claims
1. Pharmaceutical drug delivery composition comprising
- a liquid hypotonic solution of at least one hydrophilic polymer of the type which undergoes liquid-gel phase transition gelling in situ in contact with a physiological solution, and
- at least one pharmaceutically active compound.
2. Composition according to claim 1, wherein the concentration of polymer is 0.1-10 wt-%.
3. Composition according to claim 1 or 2, wherein the hydrophilic polymer is a polysaccharide, for instance gellan gum.
4. Composition according to any one of claims 1 to 3, wherein the osmolality is 25-200 mOs/kg.
5. Composition according to claim 4, wherein the osmolality is 25-150 mOs/kg.
6. Composition according to claim 5, wherein the osmolality is 50-150 mOs/kg.
7. Composition according to any one of claims 1-6, wherein the active drug is present as a solution or in the form of particles.
8. Composition according to claim 7, wherein the drug is incorporated in or associated with a polymeric matrix, complex- forming matrix, lipid matrix or ion-exchange resin.
9. Composition according to any one of claims 1-8 wherein the composition additionally contains one or more component selected from preservatives, solubilizing agents, non-ionic tonicity adjusting agents, pH-adjusting agents or complexing agents.
10. Composition according to any one of claims 1-9 which is intended for ophthalmological use and the physiological solution is lacrimal fluid or aqueous humour.
11. Method for local administration of a pharmacologically active drug characterized by the use of a composition according to any one of claims 1-10.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU69405/94A AU6940594A (en) | 1993-06-02 | 1994-06-01 | In situ gel for therapeutic use |
| JP7500555A JPH08510731A (en) | 1993-06-02 | 1994-06-01 | In situ produced gel for therapeutic use |
| EP94917868A EP0706372A1 (en) | 1993-06-02 | 1994-06-01 | In situ gel for therapeutic use |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9301877A SE9301877D0 (en) | 1993-06-02 | 1993-06-02 | IN SITU GEL FOR THERAPEUTIC USE |
| SE9301877-8 | 1993-06-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1994027578A1 true WO1994027578A1 (en) | 1994-12-08 |
Family
ID=20390132
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SE1994/000522 WO1994027578A1 (en) | 1993-06-02 | 1994-06-01 | In situ gel for therapeutic use |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0706372A1 (en) |
| JP (1) | JPH08510731A (en) |
| AU (1) | AU6940594A (en) |
| CA (1) | CA2164113A1 (en) |
| SE (1) | SE9301877D0 (en) |
| WO (1) | WO1994027578A1 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997033562A1 (en) * | 1996-03-13 | 1997-09-18 | Laboratoires Merck Sharp & Dohme-Chibret Snc | Ophthalmological composition of the type which undergoes liquid-gel phase transition |
| FR2746014A1 (en) * | 1996-03-13 | 1997-09-19 | Merck Sharp Dohme Chibret Lab | Ophthalmological composition containing pilocarpine |
| FR2754712A1 (en) * | 1996-10-17 | 1998-04-24 | Merck Sharp Dohme Chibret Lab | OPHTHALMIC COMPOSITIONS |
| WO1998023292A1 (en) * | 1996-11-29 | 1998-06-04 | Monsanto Company | Lubricious self-standing (intact) gel for oral delivery of biologically-active ingredients |
| DE102010023949A1 (en) * | 2010-06-16 | 2011-12-22 | F. Holzer Gmbh | In-situ lecithin microemulsion gel formulation |
| US8216604B2 (en) | 2003-01-10 | 2012-07-10 | Archimedes Development Limited | Method of managing or treating pain |
| CN109260146A (en) * | 2018-10-12 | 2019-01-25 | 广州大光制药有限公司 | Ophthalmic solution sodium in situ forming eye type gel eyedrop and preparation method |
| US10485757B2 (en) | 2015-01-27 | 2019-11-26 | The Johns Hopkins University | Hypotonic hydrogel formulations for enhanced transport of active agents at mucosal surfaces |
| US10568975B2 (en) | 2013-02-05 | 2020-02-25 | The Johns Hopkins University | Nanoparticles for magnetic resonance imaging tracking and methods of making and using thereof |
| US12005089B2 (en) | 2014-12-15 | 2024-06-11 | The Johns Hopkins University | CVS transplantation for treatment of bacterial vaginosis |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004189731A (en) * | 2002-11-26 | 2004-07-08 | Taisho Pharmaceut Co Ltd | Nasal drops |
| JP5304108B2 (en) * | 2007-08-30 | 2013-10-02 | 大正製薬株式会社 | Eye drops |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0227494A1 (en) * | 1985-10-03 | 1987-07-01 | LABORATOIRES MERCK, SHARP & DOHME-CHIBRET | Pharmaceutical composition of the type which undergoes liquid-gel phase transition |
| EP0437368A1 (en) * | 1990-01-12 | 1991-07-17 | LABORATOIRES MERCK, SHARP & DOHME-CHIBRET | Fluid ophthalmic composition based on lipid microparticles containing at least one active principle |
| EP0455396A1 (en) * | 1990-05-01 | 1991-11-06 | MDV Technologies, Inc. | Aqueous gel compositions and their use |
| EP0495421A1 (en) * | 1991-01-15 | 1992-07-22 | Alcon Laboratories, Inc. | Use of carrageenans in topical ophthalmic compositions |
-
1993
- 1993-06-02 SE SE9301877A patent/SE9301877D0/en unknown
-
1994
- 1994-06-01 CA CA 2164113 patent/CA2164113A1/en not_active Abandoned
- 1994-06-01 EP EP94917868A patent/EP0706372A1/en not_active Withdrawn
- 1994-06-01 AU AU69405/94A patent/AU6940594A/en not_active Abandoned
- 1994-06-01 JP JP7500555A patent/JPH08510731A/en active Pending
- 1994-06-01 WO PCT/SE1994/000522 patent/WO1994027578A1/en not_active Application Discontinuation
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0227494A1 (en) * | 1985-10-03 | 1987-07-01 | LABORATOIRES MERCK, SHARP & DOHME-CHIBRET | Pharmaceutical composition of the type which undergoes liquid-gel phase transition |
| EP0437368A1 (en) * | 1990-01-12 | 1991-07-17 | LABORATOIRES MERCK, SHARP & DOHME-CHIBRET | Fluid ophthalmic composition based on lipid microparticles containing at least one active principle |
| EP0455396A1 (en) * | 1990-05-01 | 1991-11-06 | MDV Technologies, Inc. | Aqueous gel compositions and their use |
| EP0495421A1 (en) * | 1991-01-15 | 1992-07-22 | Alcon Laboratories, Inc. | Use of carrageenans in topical ophthalmic compositions |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997033562A1 (en) * | 1996-03-13 | 1997-09-18 | Laboratoires Merck Sharp & Dohme-Chibret Snc | Ophthalmological composition of the type which undergoes liquid-gel phase transition |
| FR2746014A1 (en) * | 1996-03-13 | 1997-09-19 | Merck Sharp Dohme Chibret Lab | Ophthalmological composition containing pilocarpine |
| FR2754712A1 (en) * | 1996-10-17 | 1998-04-24 | Merck Sharp Dohme Chibret Lab | OPHTHALMIC COMPOSITIONS |
| WO1998017249A1 (en) * | 1996-10-17 | 1998-04-30 | Laboratoires Merck Sharp & Dohme-Chibret Snc | Ophthalmic compositions containing a carbonic anhydrase inhibitor and xanthan gum |
| US6264935B1 (en) | 1996-10-17 | 2001-07-24 | Laboratoires Msd - Chibret | Ophthalmic composition containing a carbonic anhydrase inhibitor and xanthan gum |
| WO1998023292A1 (en) * | 1996-11-29 | 1998-06-04 | Monsanto Company | Lubricious self-standing (intact) gel for oral delivery of biologically-active ingredients |
| US8889176B2 (en) | 2003-01-10 | 2014-11-18 | Depomed, Inc. | Method of managing or treating pain |
| US8216604B2 (en) | 2003-01-10 | 2012-07-10 | Archimedes Development Limited | Method of managing or treating pain |
| US9078814B2 (en) | 2003-01-10 | 2015-07-14 | Depomed, Inc. | Intranasal spray device containing pharmaceutical composition |
| US9814705B2 (en) | 2003-01-10 | 2017-11-14 | Depomed, Inc. | Intranasal spray device containing pharmaceutical composition |
| DE102010023949A1 (en) * | 2010-06-16 | 2011-12-22 | F. Holzer Gmbh | In-situ lecithin microemulsion gel formulation |
| US10568975B2 (en) | 2013-02-05 | 2020-02-25 | The Johns Hopkins University | Nanoparticles for magnetic resonance imaging tracking and methods of making and using thereof |
| US11633350B2 (en) | 2014-02-23 | 2023-04-25 | The Johns Hopkins University | Hypotonic microbicidal formulations and methods of use |
| US12005089B2 (en) | 2014-12-15 | 2024-06-11 | The Johns Hopkins University | CVS transplantation for treatment of bacterial vaginosis |
| US10485757B2 (en) | 2015-01-27 | 2019-11-26 | The Johns Hopkins University | Hypotonic hydrogel formulations for enhanced transport of active agents at mucosal surfaces |
| US11426345B2 (en) * | 2015-01-27 | 2022-08-30 | The Johns Hopkins University | Hypotonic hydrogel formulations for enhanced transport of active agents at mucosal surfaces |
| US20230074691A1 (en) * | 2015-01-27 | 2023-03-09 | The Johns Hopkins University | Hypotonic hydrogel formulations for enhanced transport of active agents at mucosal surfaces |
| CN109260146A (en) * | 2018-10-12 | 2019-01-25 | 广州大光制药有限公司 | Ophthalmic solution sodium in situ forming eye type gel eyedrop and preparation method |
Also Published As
| Publication number | Publication date |
|---|---|
| SE9301877D0 (en) | 1993-06-02 |
| JPH08510731A (en) | 1996-11-12 |
| EP0706372A1 (en) | 1996-04-17 |
| AU6940594A (en) | 1994-12-20 |
| CA2164113A1 (en) | 1994-12-08 |
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