WO1992019233A2 - Sustained release composition and methods of use thereof - Google Patents
Sustained release composition and methods of use thereof Download PDFInfo
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- WO1992019233A2 WO1992019233A2 PCT/US1992/003555 US9203555W WO9219233A2 WO 1992019233 A2 WO1992019233 A2 WO 1992019233A2 US 9203555 W US9203555 W US 9203555W WO 9219233 A2 WO9219233 A2 WO 9219233A2
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- 0 COC(*(C[C@@](C1OC11)I=I)[N+]([O-])O)*1C=C=* Chemical compound COC(*(C[C@@](C1OC11)I=I)[N+]([O-])O)*1C=C=* 0.000 description 1
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- 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
- A61K31/695—Silicon compounds
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- 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
- A61K47/51—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 non-active ingredient being a modifying agent
- A61K47/54—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 non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
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- 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
- A61K47/51—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 non-active ingredient being a modifying agent
- A61K47/54—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 non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
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- 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
- A61K47/51—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 non-active ingredient being a modifying agent
- A61K47/56—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
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Abstract
The present application relates to lipophilic conjugates of pharmaceutical compounds in admixture with a pharmaceutical vehicle not soluble in an aqueous solvent, such as a silicone oil useful as a sustained released pharmaceutical composition and methods for the treatment of medical disorders by administering an effective amount of such a sustained release pharmaceutical composition. In this invention a wide variety of pharmaceutical compounds are conjugated with the carrier and placed in admixture with a silicone oil. Acceptable compounds for conjugation with the carrier in this release delivery system include, for example, steroids (e.g., dexamethasone, prednisolone and related compounds), anti-neoplastic agents and/or ophthalmic agents (5-Fluorouracil, adriamycin and related compounds), anti-viral agents (ganciclovir, trifluorothymidine and related compounds), nonsteroidal anti-inflammatory agents (flurbiprofen, indomethacin and related compounds), anti-mitotic drugs (colchicine taxol and related compounds), drugs that act on actin polymerization (phalloidin, cytochlasin B and related compounds). Suitable lipophilic carrier molecules include long branched or unbranched alkyl chains. These chains may be saturated or unsaturated and may contain heteroatoms. Silicone chains may also be used.
Description
/
SUSTAINED RELEASE COMPOSITION AND METHODS OF USE THEREOF
Technical Field
The present application relates to lipophilic conjugates of pharmaceutical compounds in admixture with a vehicle insoluble in an aqueous solvent, such as silicone oil, useful as a sustained released pharmaceutical composition and methods for the treatment of medical disorders by administration of such a sustained release pharmaceutical composition.
Background Art Many pharmaceutical compounds are toxic in the dosage required to treat various disorders or diseases. In order to produce a therapeutic effect and maintain the therapeutic effect for an effective amount of time, a high initial dose is often required for various pharmaceutical medications.
Accordingly, there is a need for an improved sustained release system from which pharmaceutical compositions can be selectively released. This is particularly true in the area of ophthalmology. A number of drug delivery techniques have been used for administering such toxic compounds, including solid sustained release delivery systems. However, solid sustained release systems often have the drawback of
requiring surgical implantation in the eye. An improved sustained release pharmaceutical composition would be a significant advancement in this art.
For example, 5-Fluorouracil is a toxic compound which is widely used as an anti-tumor agent and in ophthalmology. However, its clinical use is largely restricted to parenteral, in particular intravenous, administration. This has been documented by DeVita and Rosenburg, Principle and Practice of Oncology, Third Edition (1989), pages 359-362.
Because of high toxicity, 5-Fluorouracil is not yet considered to be a favorable anti-cancer agent and improvement has been recognized as necessary.
5-Fluorouracil has also been used in ophthalmology for the treatment of refractory glaucoma. 5- Fluorouracil (either as topical drops or as subconjunctival injections) is used in treating refractory glaucoma to prevent scar formation following eye surgery. Clinical results have shown that repeated conjunctivial injections of 5-Fluorouracil can reduce proliferation of scar tissue and improve the success rate of filter surgery in glaucoma. See Alwad et al, Fluorouracil Filtering Surgery Study, One Year Follow- Up, American Journal of Ophthalmology 108:65-635, 1989. The use of 5-Fluorouracil in ophthalmic treatment is, however, accompanied by toxic side effects, particularly to the cornea and conjunctivia of the eye. It is thought in this technology area that these toxic side effects are caused by the high doses of 5- Fluorouracil that must be administered in order to have an effective amount of the drug available to treat the proliferation of scar tissue and improve the success rate of the filter surgery in glaucoma. From data published by Fantes et al, Topical Fluorouracil,
Pharmacokinetics in Normal Rabbit eyes, Arch. Ophthalmology 103:953-955 (1985), the half life of 5- Fluorouracil in ocular tissues can be estimated as two hours in the vitreous humor (the fluid inside the eye and behind the lens) and one hour in the aqueous humor (the fluid inside the eye and in front of the lens). This indicates that therapeutic drug levels are maintained for a comparatively short period of time even after a large initial dose. The publication further suggests that large amounts of 5-Fluorouracil must be repeatedly administered in order to achieve the desired effect.
The alternative to the repeated injections of large amounts of 5-Fluorouracil is to provide a sustained release delivery system that could maintain low therapeutic levels of 5-Fluorouracil without giving potentially toxic peak levels. Specifically, sustained release delivery systems due to solid, implantable delivery devices have been reported. See Blandford et al, " 5-Fluorouracil Sustained Release Device Implantation, Toxicology and Histology in Rabbits", Journal of Investigative Ophthalmology Visual Sciences, 31:591 (1990). However, treatment with solid delivery devices can require surgical implantation, produce unnecessary trauma to the eye, provide additional scarring and cause toxicology problems due to the delivery device being within the eye. Further, the solid delivery device may require surgical removal after exhaustion of the drug. 5-Fluorouracil has also been suggested for use in the treatment of proliferative vitreoretinopathy (PVR) . See Stern et al, "Fluorouracil Therapy for Proliferative Vitreoretinopathy After Vitrectomy" , American Journal of Ophthalmology 986:33-42 (1983).
Concerns continues to exist in this technology area as to the safety of the drug 5-Fluorouracil and retinal toxicity has been observed (See, lunig et al, "Inhibition of Experimental Intraocular Proliferation with Intravenous 5-Fluorouracil" , Ophthalmologica, 188:248-258 (1984).
As with the glaucoma filtering surgery and with the treatment of PVR, the retinal toxicity is caused by the high peak levels of 5-Fluorouracil found in the vitreous after intravitreous injections. As noted above, the repeated injections of 5-Fluorouracil are likely to be problematic due to the toxicological effects of high doses.
Further, as noted above, use of solid implantable delivery devices for sustained release of 5-
Fluorouracil has serious drawbacks and creates trauma to the eye as a result of the required surgical implantation.
Accordingly, there is a need in the art for an improved injectable sustained release delivery system
(particularly in the art area related to 5-
Fluorouracil) which is capable of maintaining low, therapeutic drug levels without requiring solid implantable devices and without causing toxicological side effects due to the sustained release delivery system. Such a system which is capable of maintaining low therapeutic drug levels of pharmaceuticals would offer significant and important advantages over existing therapies, especially in the administration of 5-Fluorouracil, for example.
Disclosure of the Invention
An object of the present invention is to provide a sustained release system for pharmaceuticals by forming
lipophilic conjugates of lipophilic carrier compounds covalently bonded to pharmaceutical compounds and then placing the conjugates in admixture with a vehicle insoluble in an aqueous solvent, such as a silicone oil.
.Another object of the present invention is to provide an improved sustained release pharmaceutical composition for 5-Fluorouracil wherein lipophilic conjugates of 5-Fluorouracil are formed and then placed in admixture with a silicone oil.
A particular object of the present invention is to provide a sustained release pharmaceutical composition of 5-Fluorouracil which delivers a low, therapeutic drug level which avoids or reduces retinal toxicity and avoids drawbacks due to solid implantable sustained delivery devices.
Still another object of the invention is to provide an .improved method for the treatment of an ophthalmic disorder or disease by administering an effective amount of a lipophilic pharmaceutical conjugate/silicone oil sustained release pharmaceutical composition to a host with an ophthalmic disorder or disease.
A still further object of the present invention is to provide an improved method for treating refractory glaucoma by administering a sustained release composition of a lipophilic 5-Fluorouracil conjugate in silicone oil to a patient to reduce the proliferation of scar tissue and improve the success rate of filter surgery in the treatment of glaucoma.
A yet further object of the present invention is to provide an improved method for treating PVR by administering a sustained release composition of a lipophilic 5-Fluorouracil conjugate in silicone oil to
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a patient needing treatment of retinol detachments and thereby avoiding the proliferation of fibroblasts and pigmented epithelial cells within the vitreous humor of the eye, thus preventing occlusion of vision and further detachment of the retina.
Brief Description of the Invention
The present invention relates to a sustained release pharmaceutical composition comprising a pharmaceutically effective amount of a lipophilic conjugate of a lipophilic carrier covalently bonded to a pharmaceutical compound in admixture with a silicone oil. Particularly preferred are sustained release compositions wherein the covalently bonded pharmaceutical compound is 5-Fluorouracil. In accordance with this invention there are provided preferred sustained release pharmaceutical compositions of a 5-Fluorouracil conjugate having the following formula
wherein R is selected from the group consisting of a ^4~^3Ω straight or branched chain alkyl group optionally containing a hetero atom; a C4-C,0 straight or branched chain alkenyl group optionally containing a hetero atom; and a C4- straight or branched chain
alkynyl group optionally containing a hetero group; or R is a lipophilic silicone chain.
Even more preferred are compounds having the formula:
wherein n is a number from 11-29 .
Still further preferred are compounds according to Formula II wherein n is a number from 15-20. Even more preferred are compounds according to formula II where n is the number 14 or 16.
The invention also relates to a method for treating an ophthalmic disorder comprising the administration of an effective amount of a sustained release pharmaceutical composition comprising an eff ective amount of a lipophilic conjugate of a l i p ophi l i c c arrier c ova l ently b onded t o a pharmaceutical compound in admixture with a silicone oil . The invention further relates to a method for treating refractory glaucoma by administering an ef f ective amount of a composition a lipophilic conjugate of a lipophilic carrier covalently bonded to a pharmaceutical compound in admixture with a silicone oil , wherein the conjugate of the carrier and the pharmaceutical compound is a 5-Fluorouracil/carrier conjugate having the following formula
wherein R is selected from the group consisting of a C4-C30 straight or branched chain alkyl group optionally containing a hetero atom; a C,-C,0 straight or branched chain alkenyl group optionally containing a hetero atom; and a C,-C30 straight or branched chain alkynyl group optionally containing a hetero group; or R is a lipophilic silicone chain, to a patient to reduce the proliferation of scar tissue and improve the success rate of filter surgery in the treatment of glaucoma.
The invention still further relates to a method for treating proliferative vitreoretinophthy by administering an effective amount of a lipophilic conjugate of a lipophilic carrier covalently bonded to a pharmaceutical compound in admixture with a silicone oil, wherein the conjugate of the carrier and the pharmaceutical compound is a 5-Fluorouracil/carrier conjugate having the following formula
wherein R is selected from the group consisting of a C4-C3Q straight or branched chain alkyl group optionally containing a hetero atom; a C4-C30 straight or branched chain alkenyl group optionally containing a hetero atom; and a C4-C3Q straight or branched chain alkynyl group optionally containing a hetero group; or R is a lipophilic silicone chain, to a patient needing treatment and thereby avoiding the proliferation of fibroblast and pigmented epithelial cells within the vitreous humor of the eye and thus preventing oclusion of vision and further detachment of the retina.
Brief Description of the Drawings
Figure 1 relates to a general illustration of how the sustained release drug carrier system works at the interface of the body fluid and the sustained release pharmaceutical composition.
Figure 2 further illustrates the sustained release system by taking into consideration effects due to a slight solubility of some drug/carrier conjugates in some body fluids.
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Figure 3 illustrates generally a sample apparatus for measuring rates of release of a pharmaceutical compound from the sustained release composition.
Figure 4 illustrates the release of 5-Fluorouracil from the conjugate/silicone oil composition into a buffered N-nonanol solution; the steady state release rate was 0.13 +/- 0.003 UG/Hr and the conjugate used was
5-FU COO(CH2)8CH3. Detailed Description of the Invention and Preferred
TCrnbnr- ■ ■mta-n-fcg
In accordance with this invention there are disclosed sustained release pharmaceutical compositions comprising conjugates of lipophilic carriers (for example, alkoxycarbonyl) of a wide variety of pharmaceutical compounds in admixture with a silicone oil. This conjugate/silicone oil composition provides an improved sustained release delivery system. Acceptable compounds for conjugation with the carrier include, for example, steroids (e.g., dexamethasone, prednisolone and related compounds), anti-neoplastic agents and/or ophthalmic agents (5-Fluorouracil, adriamycin and related compounds) anti-viral agents (ganciclovir, trifluorothymidine and related compounds) nonsteroidal anti-inflammatory agents (flurbiprofen, indomethacin and related compounds, anti-mitotic drugs (colchicine taxol and related compounds) drugs that act on actin polymerization (phalloidin, cytochlasin B and related compounds).
Suitable carrier molecules include long chain branched or unbranched alkyl chains. These alkyl chains may be saturated or unsaturated and may contain heteroatoms. Silicone chains may also be used. The only essential requirements are that the non-toxic lipophilic carrier should be substantially insoluble in an aqueous medium, that the solubility of the drug/carrier conjugate should be extremely low in an
SUBSTITUTESHEET
H
aqueous media and that the drug/carrier bond should be labile in an aqueous media.
In accordance with this invention. there are provided sustained release pharmaceutical compositions comprising an effective amount of a lipophilic conjugate of a lipophilic carrier covalently bonded to a pharmaceutical compound in admixture with a silicone oil.
The present invention provides a sustained release pharmaceutical composition comprising an effective amount of a lipophilic conjugate of a lipophilic carrier covalently bonded to a pharmaceutical compound in admixture with a silic.one oil, wherein the lipophilic carrier covalently bonded to the pharmaceutical compound is selected from the group consisting of a C4-C3Q straight or branched chain alkyl group optionally containing a hetero atom; a C4-C30 straight or branched chain alkenyl group. optionally containing a hetero atom; and a C4-C30 straight or branched chain alkynyl group optionally containing a hetero group; or a lipophilic silicone chain.
The present invention also preferably provides a sustained release pharmaceutical composition comprising an effective amount of a lipophilic conjugate of a lipophilic carrier covalently bonded to a pharmaceutical compound in admixture with a silicone oil, wherein the conjugate of the carrier and the pharmaceutical compound is a 5-Fluorouracil/carrier conjugate having the following formula
IZ
wherein R is selected from the group consisting of a C4-C30 straight or branched chain alkyl group optionally containing a hetero atom; a 4-C30 straight or branched chain alkenyl group optionally containing a hetero atom; and a C4-C30 straight or branched chain alkynyl group optionally containing a hetero group; or R is a lipophilic silicone chain.
Even more preferred are sustained release pharmaceutical compositions comprising 5- Fluorouracil/carrier conjugates according to Formula I wherein said conjugates have the following formula
wherein n is a number from 11 to 29. Particularly preferred of such compositions are compositions wherein n is the number from 15-20. Still further preferred are such compositions wherein n is selected from the numbers 14 or 16.
( 3
Further, the preferred pharmaceutical compositions of the present invention provide an injectable sustained release delivery system for 5-Fluorouracil capable of maintaining low, therapeutic drug levels. In the preferred sustained release pharmaceutical system described above, 5-Fluorouracil is covalently bound to a high lipophilic carrier molecule to provide a 5-Fluorouracil conjugate and dissolved in silicone oil. The modified silicone oil can then be injected into the vitreous humor in the normal way that 5- Fluorouracil is injected for treating, for example, in treating refractory glaucoma or PVR.
This sustained release system of this invention offers advantages over treatment with 5-Fluorouracil alone since the number of injections is minimized due to the sustained release so that the toxicological effects of the high peak doses of 5-Fluorouracil are avoided. The advantage over the solid implantable sustained release delivery devices is that the present injectable sustained release pharmaceutical compositions do not require surgical implantation or possible surgical removal. Hence, the toxic side- effects are avoided.
The lipophilic 5-Fluorσuracil conjugate according to the invention is either insoluble or is of very low solubility in the vitreous humor and cannot substantially escape from the oil. Accordingly, solubility of the conjugate in the vitreous is limited and the 5-Fluorouracil cannot move from the oil into the vitreous very readily. Once in the vitreous the covalent bond between the carrier and the 5- Fluorouracil conjugate is labile so that it can be rapidly cleaved tc regenerate 5-Fluorouracil and the carrier molecule. The carrier molecule will then move
\6r
back into the oil where it is much more soluble and the 5-Fluorouracil is free in the vitreous to treat the disorder in the eye. Due to the low solubility of the 5-Fluorouracil/carrier conjugate in the vitreous as noted above, most of the breaking of the 5- Fluorouracil/carrier conjugate bond to regenerate the carrier and the free 5-Fluorouracil sill take place at the oil/vitreous interface. See, Figures 1 and 2.
As described above and shown in Figures 1 and 2, free 5-Fluorouracil is slowly released into the vitreous and both the free carrier and 5- Fluorouracil/carrier conjugate remain substantially in the silicone oil. This slow release of 5- Fluorouracil avoids the toxicological side-effects of high 5-Fluorouracil doses while maintaining the desired therapeutic effects.
As is clear from Figure 1 the labile drug/carrier covalent bond is cleaved to release the drug into the body fluid and retain the carrier within the pharmaceutical composition. Specifically, the drug carrier within the silicone oil at location 1 diffuses to the surface at location 2 where the drug protrudes from the interface of the oil and the body fluid; at position 3, cleavage occurs and the carrier remains within the oily vehicle while the drug is released into the body fluid; and at position 4 the carrier released from the conjugate diffuses further into the oily vehicle to remain there while the released drug diffuses further into the body fluid to effect treatment.
As is shown in Figure 2 the solubility of drug/carrier conjugates is so low that only a small amount of the drug/carrier conjugate will be soluble in the body fluid. The drug carrier conjugate which is
slightly soluble in the body fluid moves outside the silicone oil into the body fluid where it is then cleaved to release the drug into the body fluid followed by the carrier moving back into the silicone oil. Specifically, the drug carrier conjugate at location 1 within the silicone oil moves to position 2 in very small amounts; at position 3 the carrier drug is quickly cleaved since the drug/carrier bond is labile in the body fluid; and at position 4 the lipophilic carrier portion of the conjugate migrates rapidly back into the oil where it is much more soluble while the drug moves on to the treatment cite in the body fluid to effect treatment.
As indicated above, the sustained release pharmaceutical composition of 5-Fluorouracil/carrier conjugate in silicone oil can be useful in treating refractory glaucoma to prevent scar formation following eye surgery and improve the success rate of the filter surgery in glaucoma. The toxic side effects of repeated injections and the drawbacks of solid implantable delivery devices are avoided by use of the present sustained release composition.
The sustained release compositions according to the present invention can be used for the treatment of PVR by intravitreous injections.
Moreover, the sustained release delivery system of a 5-Fluorouracil/carrier conjugate in silicone oil can be used to treat a wide variety of disorders wherein 5- Fluorouracil is required.
Preparation of conjugates according to formula 1 and sustained release pharmaceutical compositions comprising the conjugates are provided below.
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Example 1 Preparation of 1-alkoxycarbonyl conjugate of 5-Fluorouracil
Conjugates are prepared by reacting 5-Fluorouracil
(from Fluka, AG, Switzerland) with the alkyl chloroformate of the corresponding alkyl alcohol.
Preparation of the Fluorouracil
At -10°C 0.018 moles of 1-octadecanol in acetonitrile was added to 0.016 mole phosgene (20% solution in toluene) over 15 minutes while stirring with a magnetic stirrer. The mixture was then stirred at room temperature for approximately 14 hours and then dried in vacuo.
Conjugation of the Chloroformate with 5-Fluorouracil In a toluene/acetonitrile solvent system 0.004 mole of 5-Fluorouracil was added to 0.005 of the alkyl chloroformate prepared above. To this 0.006 moles of pyridine in 10 ml of acetonitrile were added at 0°C. The mixture was then stirred at 60°C for 24 hours and then allowed to cool to room temperature. After evacuation in vacuo 50 ml of 0.1N HC1 was added to the residue and the conjugate was extracted by ethyl acetate. The organic phase was then dried over sodium sulfate and evaporate in vacuo. The solid obtained was purified by recrystallization from ethyl acetate-light petroleum solvent. The yield was approximately 50% and the melting point of the product was 93-95°C.
The above procedure was followed using 1- hexadecanol instead of 1-octadecanol. Again, the yield was approximately 50%.
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Example 2 Measurement of Drug Release
The release of 5-Fluorouracil from the conjugate was simulated in n-Nonanol.
Release into Buffer The release of 5-Fluorouracil into isotonic buffered solution (pH 7.4) at 37°C was measured using the apparatus shown in Figure 3. Silicone oil containing a 5-Fluorouracil/carrier conjugate was loaded into the donor compartment and samples of the reservoir were periodically removed for analysis by high pressure liquid chromontography (HPLC). The results are shown in Figure 4. Other drug/carrier conjugates will produce similar results. Similar experiments are performed using serum and vitreous as the receptor solution. The release rates are slightly different than those obtained in the nonanol buffer due to increased solubility of the drug/carrier complex in serum and vitreous and more rapid cleavage of the drug barrier. The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept and therefore such adaptations are intended to be comprehended within the meaning and range of equivalents of a disclosed embodiment. It is to be understood that the phraseology or terminology employed herein is for the purposes of description only and not of limitation.
Claims
1. A sustained release pharmaceutical composition comprising a pharmaceutically effective amount of a lipophilic conjugate of a lipophilic carrier covalently bonded to a pharmaceutical compound in admixture with a pharmaceutical vehicle insoluble in an aqueous solvent.
2. A pharmaceutical composition according to claim 1, wherein said covalently bonded pharmaceutical compound is 5-Fluorouracil and said vehicle is a silicone oil.
3. A pharmaceutical composition according to claim 1, wherein said lipophilic carrier covalently bonded to said pharmaceutical compound is selected from the group consisting of a C4-C30 straight or branched chain alkyl group optionally containing a hetero atom; a C4-C30 straight or branched chain alkenyl group optionally containing a hetero atom; and a C4-C30 straight or branched chain alkynyl group optionally containing a hetero group; or a lipophilic silicone chain.
4. A pharmaceutical composition according to claim 1, wherein said conjugate of said carrier and said pharmaceutical compound is a 5- Fluorouracil/carrier conjugate having the following formula
wherein R is selected from the group consisting of a C4-C,0 straight or branched chain alkyl group optionally containing a hetero atom; a C4-C30 straight or branched chain alkenyl group optionally containing a hetero atom; and a C4-C30 straight or branched chain alkynyl group optionally containing a hetero group; or R is a lipophilic silicone chain and said vehicle is a silicone oil.
5. A pharmaceutical composition according to claim 4 , where said conjugate has the following formula
wherein n is a number from 11 to 29
6. A pharmaceutical composition according to claim 5, wherein n is a number from 15-20.
7. A pharmaceutical composition according to claim 5, wherein n is selected from the numbers 14 or 16.
8. A method for treating an ophthalmic disorder comprising the administration of an effective amount of a composition according to claim 1 to a patient in need thereof.
9. A method for treating refractory glaucoma by administering an effective amount of a composition according to claim 4 to a patient to reduce the proliferation of scar tissue and improve the success rate of filter surgery.
10. A method for treating proliferative vitreoretinophthy by administering a sustained release composition according to claim 4 to a patient needing treatment, thereby avoiding the proliferation of fibroblast and pigmented epithelial cells within the vitreous humor of the eye and preventing oclusion of vision or further detachment of the retina.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US69322891A | 1991-04-29 | 1991-04-29 | |
| US693,228 | 1991-04-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1992019233A2 true WO1992019233A2 (en) | 1992-11-12 |
| WO1992019233A3 WO1992019233A3 (en) | 1993-01-07 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1992/003555 WO1992019233A2 (en) | 1991-04-29 | 1992-04-29 | Sustained release composition and methods of use thereof |
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|---|---|
| AU (1) | AU2025092A (en) |
| WO (1) | WO1992019233A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994013324A1 (en) * | 1992-12-16 | 1994-06-23 | Vestar, Inc. | Lipid prodrugs for oral administration |
| US5919762A (en) * | 1993-12-02 | 1999-07-06 | Basf Aktiengesellschaft | Conjugates of hirudin and lipophilic compounds |
| US11931415B2 (en) * | 2016-08-09 | 2024-03-19 | The University Of Liverpool | Ophthalmic compositions |
-
1992
- 1992-04-29 WO PCT/US1992/003555 patent/WO1992019233A2/en active Application Filing
- 1992-04-29 AU AU20250/92A patent/AU2025092A/en not_active Abandoned
Non-Patent Citations (1)
| Title |
|---|
| ARCHIVES OF OPHTHAMOLOGY, Vol. 104, March 1986, pp. 431-434. * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5411947A (en) * | 1989-06-28 | 1995-05-02 | Vestar, Inc. | Method of converting a drug to an orally available form by covalently bonding a lipid to the drug |
| US5484809A (en) * | 1989-06-28 | 1996-01-16 | Vestar, Inc. | Prodrugs for oral administration containing taxol or substituted taxol covalently bound to a phospholipid |
| US5744592A (en) * | 1989-06-28 | 1998-04-28 | Nexstar Pharmaceuticals, Inc. | Lipid prodrugs for oral administration |
| US5827831A (en) * | 1989-06-28 | 1998-10-27 | Nexstar Pharmaceuticals, Inc. | Lipid nucleotide analog prodrugs for oral administration |
| WO1994013324A1 (en) * | 1992-12-16 | 1994-06-23 | Vestar, Inc. | Lipid prodrugs for oral administration |
| US5919762A (en) * | 1993-12-02 | 1999-07-06 | Basf Aktiengesellschaft | Conjugates of hirudin and lipophilic compounds |
| US11931415B2 (en) * | 2016-08-09 | 2024-03-19 | The University Of Liverpool | Ophthalmic compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1992019233A3 (en) | 1993-01-07 |
| AU2025092A (en) | 1992-12-21 |
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