MXPA97009606A - Liquid system of controlled release and viscosity elev - Google Patents
Liquid system of controlled release and viscosity elevInfo
- Publication number
- MXPA97009606A MXPA97009606A MXPA/A/1997/009606A MX9709606A MXPA97009606A MX PA97009606 A MXPA97009606 A MX PA97009606A MX 9709606 A MX9709606 A MX 9709606A MX PA97009606 A MXPA97009606 A MX PA97009606A
- Authority
- MX
- Mexico
- Prior art keywords
- composition
- controlled release
- carrier material
- saib
- biologically active
- Prior art date
Links
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Abstract
The present invention relates to a composition for the controlled release of a substance that includes: (i) a liquid, water-insoluble, non-polymeric carrier material (HVKCM) of viscosity of at least 5,000 cP at 37 ° C, which does not crystallize in environmental or physiological conditions, and (ii) a substance that is going to be released
Description
CONTROLLED RELEASED AND HIGH VISCOSITY LIQUID SYSTEM This invention relates to a liquid composition of high viscosity useful for releasing substances and for other applications, including tissue coating and prevention of adhesions.
BACKGROUND OF THE INVENTION The area of controlled release, biodegradable systems for bioactive compounds is now widely investigated. Biodegradable matrices for the administration of drugs are useful because they omit the need to separate the spent device from medication. The most common matrix materials for drug supply are polymers. The field of biodegradable polymers has developed rapidly due to the • synthesis and • biodegradability of polylactic acid as reported by Kulkarni et al., In 1966 ("Polylactic acid for surgical implants", Arch. Surg., 93: 839) . Examples of other polymers that have been reported as useful as a matrix material for release devices include polyanhydrides, polyesters such as polyglycolides and polylactide-co-glycolides, polyamino acids such as polylysine, polymers and copolymers of polyethylene oxide,
P1607 / 97MX polyethylene finished in acrylic, polyamides, polyurethanes, polyorthoesters, polyacrylonitriles and polyphosphazenes. See, for example, U.S. Patent Nos. 4,891,225 and 4,906,474 to Langer (polyanhydrides), 4,767,628 to Hutchinson (polylactide, polylactide-co-glycolide acid) and 4,530,840 to Tice, et al. (polylactide, polyglycolide and copolymers). Degradable materials of biological origin are well known, for example, cross-linked gelatin. Hyaluronic acid has been crosslinked and used as a degradable dilator polymer for biodicidal applications (US Pat. No. 4,957,744 to Della Valle et al., 1991) "Surface modification of polymeric bio aterials for reduced thro bogenicity", Polym. Mater. Sci. Eng. , 62: 731-735]). Biodegradable hydrogels have also been developed for use in the controlled release of drugs as carriers of biologically active materials such as hormones, enzymes, antibiotics, antineoplastic agents and cell suspensions. The temporary conservation of the functional properties of a carrier species has been achieved, as well as the controlled release of the species in the local tissues or the systemic circulation. See, for example, U.S. Patent No. 5,149,543 to Cohen. The proper choice of
P1607 / 97MX macro hydrogel can produce membranes with a range of permeability, pore size and degradation rates suitable for a variety of applications in surgery, diagnosis and medical treatment. Different dispersion systems are currently in use as, or are being explored for use, carriers of substances, particularly biologically active compounds. The dispersion systems that are used for pharmaceutical and cosmetic formulations can be classified as suspensions or emulsions. Suspensions are defined as solid particles with size in the range from a few nanometers to hundreds of microns, dispersed in a liquid medium using suspending agents. The solid particles include microspheres, microcapsules and nanospheres. Emulsions can be defined as dispersions of one liquid in another, stabilized by an interfacial film of emulsifiers such as lipid surfactants. . Formulations of the emulsions include water-in-oil and oil-in-water emulsions, multiple emulsions, microemulsions, microdroplets and liposomes. The microdroplets are unilamellar phospholipid vesicles consisting of a spherical lipid layer with an oil phase within, as defined in U.S. Patent Nos. 4,622,219 and 4,725,442 issued to Haynes. Liposomes are vesicles
P1607 / 97MX phospholipids that are prepared by mixing polar lipids insoluble in water with an aqueous solution. The unfavorable entropy caused by the mixing of the insoluble lipid in the water produces a highly ordered set of closed concentric membranes of phospholipids with trapped aqueous solution. U.S. Patent No. 4, 938,763 to Dunn, et al., Discloses a method for forming an in situ implant by dissolving a non-reactive thermoplastic polymer, insoluble in water in a biocompatible solvent, soluble in water to form a liquid, placing the liquid within the body and dissipation of the solvent to produce a solid implant. The polymer solution can be placed in the body through a syringe. The implant can take the shape of the cavity that surrounds it. In an alternative embodiment, the implant is formed from liquid oligomeric polymers, reagents that do not contain solvent and that harden the place to form solids, usually with the addition of a catalyst for curing. Although various materials have been evaluated for use in the controlled release of substances, there is still a need to provide simpler systems with little toxicity for the controlled release of substances. The release systems described in
P1607 / 97MX above, for example, require the preparation of charged polymers and polymer matrices, or hydrogels, or other complex or fragile compositions. In particular, there is a need to provide a liquid-based release system that is easily formulated with a substance to be released and that can be easily administered. Therefore, an object of the present invention is to provide a simple system for the release of substances. Another object of the invention is to provide a liquid-based release system which is easily formulated with a substance to be released and which is easily administered. Another object of the present invention is to provide a method for the controlled release of substances in a simple liquid-based system.
COMPENDIUM OF THE INVENTION A composition for the controlled release of substances is provided which includes: (i) a high viscosity liquid, water-insoluble, non-polymeric carrier material (HVLCM) of viscosity of at least 5,000 cP at 37 ° C which do not crystallize under environmental or physiological conditions; and (ii) a substance to be released.
P1607 / 97MX In one embodiment, the HVLCM is mixed with a water-soluble or water-miscible solvent such as ethanol, dimethyl sulfoxide, ethyl lactate, ethyl acetate, benzyl alcohol, triacetin, N-methylpyrrolidone, propylene carbonate. , glycofurol, freons such as trichlorofluoromethane and dichlorofluoromethane, dimethyl ether, propane, butane, dimethylformamide, dimethylacetamide, diethylene carbonate, butylene glycol, N- (betahydromethyl) lactamide, diocholanes and other amides, esters, ethers, alcohols, to form a liquid carrier material of lower viscosity (LVLCM), which is mixed with the substance to be released, before administration. In a preferred embodiment, the HVLCM has a viscosity less than 1000 cP. For administration the composition is placed in the body or on a surface, and the solvent is dissipated or diffused from the LVLCM by forming in situ a highly viscous implant or composition that releases the substance over time. • Through a selection-adesuada of the solvent and the HVLCM can achieve a wide variety of viscosities for the composition before and after the administration. In a preferred embodiment, the HVLCM is biodegradable. In one embodiment, the substance that is mixed with the HVLCM is a biologically active substance useful for human therapy, veterinary therapy or for purposes
P1607 / 97MX agricultural. In the agricultural area, for example, the composition with the suitable active agents can be applied on the areas for the control of weeds (for example diquat), insects (for example, methyl parathion), or pests. In the veterinary area, the composition can be used, for example, to release mixed steroids as growth promoters for cattle, or to release vaccines (such as the parvovirus vaccine for post-swine protection of pigs). In humans the composition can be used to release a wide range of biologically active substances, which are described in greater detail below, or alternatively can be used with or without active agents to block surgical adhesions or for scaffolding in filling gaps, or to guide products for the regeneration of tissue, such as the periodontal membrane. In another example, the compositions can be injected into the arterial supply of a tumor, where it would form a highly viscous implant that would block the blood supply of the tumor. In another example, the composition can be used as a tissue adhesive, with or without sutures. In another example, the composition can be used as a partially occlusive cover for wounds. The in vivo implants of the composition can be placed anywhere within the body,
P1607 / 97MX included vascular tissue as muscle or fat; rigid tissue such as bone; a cavity, including but not limited to the periodontal, oral, vaginal, rectal or nasal cavity; or a sac like the periodontal sac or the bottom of the eye sac. The composition optionally includes additives that modify the properties of the composition as desired. Non-limiting examples of suitable additives include biodegradable polymers, non-biodegradable polymers, natural or synthetic oils, carbohydrates or carbohydrate derivatives, inorganic salts BSA (bovine serum albumin), surfactants and organic compounds such as sugar, and organic salts such as citrate sodium. In general, the less soluble in water, ie, the more lipophilic, the additive, the more the rate of release of the substrate will decrease, compared to the same composition without the additive. In one embodiment, it is convenient to use additives that increase the properties such as strength or porosity of the composition. In one embodiment, the HVLCM or LVLCM is used in combination with an additive and without substrate to be released. In an alternative embodiment, the HVCLM / substrate composition is included in a second carrier material, for ease of storage, handling, supply, or
P1607 / 97MX another way to modify one or more of the properties of the composition. Non-limiting examples of the second carrier materials are liquids in which the HVLCM (form an emulsion) is not soluble, solids, gel formulations and transdermal delivery systems. The substrate must have high solubility in the HVLCM and low solubility in the second carrier material. For example, an emulsion of HVC114 / substrate in water can be provided. A useful emulsion falls within this invention as a mouth rinse, in which the substrate is an active agent for the treatment of halitosis, oral infections or other oral disorders. In another embodiment, HVLCM is used as a carrier for the topical administration of a substrate. For example, HVLCM can help the solubility and dermal transport of biologically active agents. In another example, the HVLCM can be used as a carrier for an insect repellent containing DEET -. * In another embodiment, the HVLCM is used to release compounds for hair or scalp, for example compounds against hair parasites or anti-dandruff, or therapeutic compounds.
BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a graph of the release of methylene blue from SAIB (isobutyrate acetate of
P1607 / 97MX sucrose) when measured in percent release over time (hours) (80% SAIB, dark circle, 85% SAIB, triangle pointing down, dark, 90% SAIB, light box, 95% SAIB, triangle pointing up). Figure 2 is a graph of the release of theophylline from SAIB when measured in release (mg / mg) over time (hours) (0.5% theophylline, dark circle, 1.0% theophylline, triangle pointing down, 2.5% theophylline, dark picture, 5.0% theophylline, triangle pointing upwards, 10% theophylline, dark diamond). Figure 3 illustrates the effect of sucrose on the release of methylene blue from SAIB 90% in percent release over time in hours (dark circle, 0% sucrose (90% SAIB, 10% ETOH); triangle pointing down, 2.5% sucrose (90% SAIB, 7.5% ETOH), dark box, 5.0% sucrose (90% SAIB, 5% EtOH)). Figure 4 illustrates the effect of. CAB .. (cellulose acetate butyrate) in the release of methylene blue from SAIB when measured in percent release over time (hours) solid circle, 5% CAB (SAIB 40%, ETOH 55%); triangle pointing down, solid, 10% CAB (40% SAIB, 50% ETOH); and solid box 15% CAB (SAIB 40%, ETOH 45%)). Figure 5 is a graph of the release of
P1607 / 97MX BSA from a paste of BSA (9%) / SAIB when measured in release (mg released) over time (hours). Figure 6 is a graph of the release of chlorhexidine from SAIB / ethyl lactate (EtLac) when measured in percent release over time (hours) (50/50 SAIB / EtLac, clear circle; 70/30 SAIB / EtLac, triangle pointing down, of course, 90/10 SAIB / EtLac, clear picture). Figure 7 is a graph of the release of chlorhexidine from SAIB / NMP when measured in percent release over time (hours) (50/50 SAIB / NMP, clear circle, 70/30 SAIB / NMP, triangle pointing down, of course, 90/10 SAIB / NMP, clear picture). Figure 8 is a graph of the release of chlorhexidine from SAIB / propylene carbonate when measured in percent release over time (hours) (64% SAIB, clear circle, 75% SAIB, triangle pointing down, clear, 85% SAIB, clear box). Figure 9 is a graph of the release of
2. 5% diclofenac from SAIB / triacetin when measured in percent release over time (hours) (50/50 SAIB / triacetin, clear circle, 70/30 SAIB / triacetin, triangle pointing down, clear; / 10 SAIB / triacetin, light box). P1607 / 97MX Figure 10 is a graph of the release of 2.5% diclofenac from SAIB / ethanol (EtOH), with and without sucrose, when measured in percent release over time (hours) (79% SAIB , clear picture; 82% SAIB, triangle pointing down, dark; 90% SAIB, dark box; 88% SAIB, triangle pointing down, of course; 88% SAIB, 2.5% sucrose, dark circle; 80% SAIB, 5% sucrose, clear circle). Figure 11 is a graph of the release of 2.5% diclofenac from SAIB / EtOH, with and without additives, CAB and cellulose acetate propionate ("CAP"), as when measured in percent release over time (hours) (no additive, light box, with CAP, triangle pointing down, clear, with CAB, clear circle). Figure 12 is a graph of the release of 2.5% diclofenac from SAIB / dimethylsulfoxide (DMSO) when measured in per. percent release during time (hours) (70/30 SAIB / DMSO, clear circle, 90/10 SAIB / DMSO, triangle pointing down, of course). Figure 13 is a graph of the release of flurbiprofen from SAIB / 45% EtOH / 5% CAB when measured in percent release over time (hours), (4.99% flurbiprofen, clear box, 9.92% flurbiprofen, dark diamond).
P1607 / 97MX Figure 14 is a graph of the release of naproxen (free acid or sodium salt) from SAIB / glycofurol when measured in percent release over time (hours) (73% SAIB, 5.2% naproxen (free acid), clear circle, 60% SAIB, 3.6% naproxen (free acid), light triangle pointing down, 52% SAIB, 4.1% naproxen (free acid), light box, 74% SAIB, 5.2% naproxen (salt) sodium), dark circle, 60% SAIB, 3.4% naproxen (sodium salt), dark triangle pointing down, 52% SAIB, 3.9% naproxen (sodium salt), dark box). Figure 15 is a graph of the release of 2.5% theophylline from SAIB (40%) / EtOH / CAB or CAP, when measured in percent release over time (hours) (5% CAB, clear circle 10% CAB, dark circle, 15% CAB, light triangle pointing down, 5% CAP, dark triangle pointing down, 10% CAP, light box, 15% - CAP, dark box). Figure 16 is a graph of the release of theophylline from SAIB / propylene carbonate when measured in percent release over time (hours) (64% SAIB, light triangle pointing down, 74% SAIB, circle dark, 84% SAIB clear circle). Figure 17 is a graph of the release of two formulations. A formulation (dark shading)
P1607 / 97MX contains 3.2% SAIB, 15.1% ETOH, 0.00395% methylene blue and the remainder diH20. The other formulation (inclined shading) was 0% SAIB, 28.9% ETOH, 0.00395% methylene blue and diH20.
DETAILED DESCRIPTION OF THE INVENTION I. Selection of High Viscosity Liquid Carrier Material. A high viscosity liquid carrier material that is not polymeric, not soluble in water, and has a viscosity of at least 5,000 cP (and optionally at least 10,000, 15,000, 20,000, 25,000 or even 50,000 cP) should be selected. at 37 ° C, which does not crystallize pure under environmental or physiological conditions. The term "water-insoluble" refers to a material that is soluble in water to a degree of less than one percent by weight under ambient conditions. In a preferred embodiment, HVLCM significantly decreases viscosity when mixed with a solvent to form an LVLCM that can be mixed with a substrate for controlled release. The LVLCM / substrate composition is usually easier to be placed in the body than a HVLCM / substrate composition, because it flows more easily into and out of syringes or other implantation means, and can be formulated as an emulsion. The LVLCM can have any viscosity
P1607 / 97MX desired It has been found that a viscosity range for LVLCM of less than about 1000 cP, and more particularly less than 200 cP, is usually useful in in vivo applications. In one embodiment, the HVLCM is a disaccharide ester, such as diacetate hexabutyrate disaccharide. In a preferred embodiment, sucrose acetate isobutyrate ("SAIB"), a sucrose molecule esterified with two acetic acids and six portions of isobutyric acid, is used as HVLCM. The structure of the SAIB is as follows.
P1607 / 97MX The SAIB is orally non-toxic and is currently used as a stabilizer in emulsions in the food industry. It is a very viscous liquid and has an unusual property that presents a drastic change in viscosity with small additions of heat or with the addition of solvents. It is soluble in a large number of biocompatible solvents. When it is in solution or in emulsion, the SAIB can be applied via injection or in an aerosol spray. The SAIB is compatible with cellulose esters and other polymers that can affect the release rate of the substance. In other embodiments, the HVLCM may be stearate esters such as those of propylene glycol, glyceryl, diethylaminoethyl and glycol, stearate amides and other long chain fatty acid amides, such as N, N'-ethylendistearamide, stearamide MEA and DEA, ethylenebisteara ida , cocoamine oxide, long chain fatty alcohols such as cetyl alcohol and stearyl alcohol ,. long chain esters such as myristyl myristate, behenyl erucate and glyceryl phosphates. In a particular embodiment, the HVLCM is acetylated sucrose distearate (Crodesta A-10). The HVLCM is present in the composition in any amount that achieves the desired effect. For example, as a tissue coating or for prevention
P1607 / 97MX adhesion, the HVLCM can be used only as a protective film or bolus, or with a substrate that improves the properties or effect of the material. HVLCM is present in controlled release compositions in an amount ranging from about 99.5 percent to about 0.20 percent by weight. HVLCM is usually present in controlled release compositions in an amount in the range from about 99.5 percent to about 10 weight percent, most commonly, between 95 and 25 percent, and most commonly between 85 and 25 percent. 45, in relation to the total weight of the composition.
II. Substance to be released. Any of the substances that present a desired property can be released using this process. Preferably, the substance is a biologically active substance. The term "biologically active substance", as used herein, refers to an organic molecule that includes a drug, peptide, protein, carbohydrate (including monosaccharides, oligosaccharides and polysaccharides), protein core, mucoprotein, lipoprotein, polypeptide or synthetic protein or a small molecule linked to a protein, glycoprotein, steroid, nucleic acid (any form of DNA, including
P1607 / 97MX the cDNA or RNA, or fragments thereof), nucleotide, nucleoside, oligonucleotides (including antisense oligonucleotides), genes, lipids, hormones, vitamins, including vitamin C and vitamin E, or combination thereof, that cause a biological effect when administered in vivo to an animal, including, but not limited to, birds and mammals, in which humans are included. The term "drug", as used herein, refers to any substance that is used internally or externally as a medicine for the treatment, cure or prevention of a disease or disorder, and includes, but is not limited to, certain suppressants. , antioxidants, anesthetics, chemotherapeutic agents, steroids (including retinoids), hormones, antibiotics, antivirals, antifungals, antiproliferatives, antihistatics, anticoagulants, anti-aging agents caused by light, melanotropic peptides, non-steroidal anti-inflammatory compounds and steroids, antipsychotics and radiation absorbers, including UV absorbers. The term biologically active substance also includes agents such as insecticides, pesticides, fungicides, rodenticides and nutrients and promoters of the
P1607 / 97MX plant growth. In one embodiment, the composition is a vaccine and the substance to be released is an antigen. The antigen can be released from a cell, bacterium or viral particle, or portion thereof. As defined herein, the antigen can be a protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleic acid or combinations thereof, which produce an immunogenic response in an animal, for example, a mammal, bird or fish. As defined herein, the immunogenic response can be humoral or mediated by the cell. In the case that the material to which the immunogenic response is to be directed is poorly antigenic, it can be conjugated to a carrier such as albumin or a hapten, using standard techniques for covalent binding, for example, with one of the different reagent kits available in the market. Examples of preferred antigens include viral proteins such as influenza protein, human immunodeficiency virus (HIV) proteins and hepatitis proteins, A, B or C, and bacterial proteins, lipopolysaccharides such as cell walls, Gram-negative bacterial cells and proteins of Neisseria gonorrhea and parvovirus. Non-limiting examples of materials
Pharmacological P1607 / 97MX include anti-infectives such as nitrofurazone, sodium propionate, antibiotics, including penicillin, tetracycline, oxytetracycline, chlorotetracycline, bacitracin, nystatin, streptomycin, neomycin, poli ixin, gramicidin, chloramphenicol, erythromycin and azithroin; sulfone idas including sulfacetamide, sulfa etizol, sulfamethazine, sulfadiazine, sulfa erazine and sulfisoxazole, and antivirals including idoxuridine; antialergenic agents such as antazoline, metapirithene, chlorpheniramine, pyrilamine, profenpyridamine, hydrocortisone, cortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, triamcinolone, medrisone, prednisolone, prednisolone sodium 21-succinate, and prednisolone acetate; desensitizing agents such as ragweed pollen antigens, hay fever pollen antigens, powder antigens and milk antigen; vaccines such as smallpox, yellow fever, distemper or panleukopenia, swine cholera, varicella, antitoxin against snake venom, scarlet fever, diphtheria toxoid, tetanus toxoid, pigeon varicella, whooping cough, rabies influenzae, mumps, sistisercosis, poliomyelitis and Newcastle; decongestants such as phenylephrine, naphazoline and tetrahydrazoline; miotics and anticholinesterases such as polycarpine, spermine salicylate, carbachol,
P1607 / 97MX diisopropyl fluorophosphate, phospholine iodide and demecarium bromide; parasympatholytics such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine and hydroxyantase; sympathomimetics such as epinephrine; sedatives and hypnotics such as sodium pentobarbital, phenobarbital, secobarbital sodium, codeine, (a-bromoisovaleryl) urea, carbromal; psychic activators such as 3- (2-aminopropyl) indole acetate and 3- (2-aminobutyl) indole acetate; tranquilizers such as reserpine, chloropromaline and thiopropazate; androgenic steroids such as methyl-testosterone and fluorimesterone; estrogens such as estrone, 17-b-estradiol, ethinyl estradiol and diethyl stilbestrol; progestational agents such as progesterone, megestrol, melengestrol, chlormadinone, ethisterone, norethinodrel, 19-norprogesterone, norethindrone, medroxyprogesterone and 17-b-hydroxy-progesterone; humoral agents such as Prostaglandins, for example PGEx, * PGE2-and -PGF2; antipyretics such as aspirin, sodium salicylate and salicylamide; antispasmodics such as atropine, metantelin, papaverine, and metescopolamine bromide; antimalarials such as 4-aminoquinolines, 8-aminoquinolines, chloroquine and pyrimethamine, antihistamines such as diphenhydramine, dihydrazinate, tripelenamine, perphenazine and chlorphenazine; Cardioactive agents such as dibenzhidroflum thiazide,
P1607 / 97MX flumetiazide, chlorothiazide and aminotrate; nutritional agents such as vitamins, peptides and natural and synthetic bioactive proteins, including growth factors, cell adhesion factors, cytokines and biological response modifiers. The active compound is included in the composition in an amount sufficient to release an effective amount in the animal or host plant to achieve a desired effect. The amount of medicament or biologically active agent incorporated in the composition will depend on the desired release profile, the concentration of the medication necessary for a biological effect and the desired release period of the medicament. The concentration of the active compound in the composition will also depend on the rates of absorption, inactivation and excretion of the drug as well as other facts known to those skilled in the art. It should also be noted that the dosage values will also vary with the severity of the condition to be alleviated. Furthermore, it must be understood that for any particular person, specific dosage regimens must be adjusted over time according to the individual need and professional judgment of the person administering or supervising the administration.
P1607 / 97MX of the compositions, and that the concentration ranges set forth herein are examples only and are not intended to limit the scope or practice of the claimed composition. The composition can be administered in a dosage or it can be divided into several smaller doses to be administered at different time intervals. The biologically active substance is usually present in the composition in the range from about 0.5 percent to about 20 weight percent relative to the total weight of the composition, and more commonly, between about 1 percent by weight. about 15 percent by weight and more. Another preferred range is from about 2 percent to about 10 percent by weight. For very active agents, such as growth factors, the preferred ranges are less than 1% by weight and less than 0.0001%. Both soluble and insoluble substances can be distributed in HVLC-M or LVLCM for controlled release.
III. Additives The addition of a variety of additives to the HVLCM or LVLCM is optional in order to modify the properties of the material as desired. The additives can be present in any quantity that is
P1607 / 97MX sufficient to impart the desired properties to the composition. The amount of additive that is used in general will depend on the nature of the additives and the effect to be achieved, and can be easily determined by the routine tester. When present, the additive is usually present in the compositions in an amount in the range from about 0.1 percent to about 20 weight percent, relative to the total weight of the composition, and more commonly, is present in the composition in an amount in the range from about 1, 2 or 5 percent to about 10 weight percent. Certain additives, such as buffer solutions, are only present in small amounts in the composition. The following categories are non-limiting examples of the kinds of additives that can be employed in the composition. Given the description herein and the objectives to be achieved, a person skilled in the art will readily know how to select other additives to achieve a desired purpose. All these modalities are considered within the described invention.
A. Biodegradable polymers. A category of additives are polymers and
P1607 / 97MX biodegradable oligomers. The polymers can be used to modify the release profile of the substance to be administered, to add integrity to the composition, or otherwise modify the properties of the composition. Non-limiting examples of suitable biodegradable polymers and oligomers include: poly (lactide), poly (lactide-co-glycolide), poly (glycolide), poly (caprolactone), polyamides, polyanhydrides, polyamino acids, polyorthoesters, polycyanoacrylates, poly (phosphazines) ), poly (phosphoesters), polyesteramides, polydioxanones, polyacetals, polycarbonates, polycarbonates, polyoxycarbonates, degradable polyurethanes, polyhydroxy strengths, polyhydroxyvalerate, polyalkylene oxalates, polyalkylene sulcuconates, poly (malic acid), chitin, chitosan, and copolymers, terpolymers, oxidized cellulose or combinations or mixtures of the aforementioned materials. Examples of the poly (α-hydroxy acid) s include poly (glycolic acid), poly (DL-lactic acid) and poly (L-lactic acid), and their copolymers. Examples of the polylactones include poly (e-caprolactone), poly (d-valerolactone) and poly (gamma-butyrolactone).
D. Non-biodegradable polymers. Another additive for use with the compositions of the
P1607 / 97MX present are non-biodegradable polymers. Non-limiting examples of non-erodible polymers that can be used as additives include: polyacrylates, ethylene-vinyl acetate polymers, cellulose and cellulose derivatives, acyl-substituted cellulose acetates and derivatives thereof, non-erodible polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, polyvinyl imidazole), chlorosulfonated polyolefins and polyethylene oxide. Preferred non-biodegradable polymers include polyethylene, polyvinyl pyrrolidone, ethylene vinylacetate, polyethylene glycol, cellulose acetate butyrate ("CABO") and cellulose acetate propionate ("CAP").
C;. Oils and. Fats Another class of additives that can be used in the compositions herein are natural and synthetic oils and fats. Oils derived from animals or seeds from walnut plants usually include glycerides of the fatty acids, mainly oleic, palmitic, stearic and linoleic. As a general rule, the higher the hydrogen content in the thicker molecule the oil becomes. Non-limiting examples of suitable natural and synthetic oils include oils
P1607 / 97MX vegetables, peanut oil, medium chain triglycerides, soybean oil, almond oil, olive oil, castor oil, peanut oil, fennel oil, camellia oil, corn oil, sesame oil, cottonseed oil and soybean oil, crude or refined and triglycerides of medium chain fatty acids. Fats are usually glyceryl esters of higher fatty acids such as stearic and palmitic. These esters and their mixtures are solid at ambient temperatures and have a crystalline structure. Lard and tallow are examples. In general, oils and fats increase the hydrophobicity of the SAIB, decreasing the rate of degradation and the uptake of water.
D. Carbohydrates and_ Carbohydrate Derivatives. Another class of additives that can be used in the compositions of the present invention are carbohydrates and carbohydrate derivatives. Non-limiting examples of these compounds include monosaccharides (simple sugars such as fructose and its glucose isomer (dextrose), disaccharides such as sucrose, maltose, cellobiose and lactose, and polysaccharides.
IV. Solvent. P1607 / 97MX When the composition is used as an LVLCM, it must contain a solvent in which the HVLCM is soluble. Preferably, the substance to be released must also be soluble in the solvent. The solvent must be non-toxic, soluble in water or miscible in water, and on the other hand biocompatible. Solvents that are toxic should not be used for pharmaceutical or agricultural purposes. The solvents that are used to inject the composition into animals should not cause significant tissue irritation or necrosis at the site of implantation, unless irritation or necrosis is the desired effect. The solvent must be at least soluble in water, so that it diffuses rapidly in bodily fluids or other aqueous media, causing the composition to coagulate or solidify. Examples of suitable solvents include ethanol, ethyl lactate, propylene carbonate, glycofurol, N-methyl pyrrolidone, 2-pyrrolidone, propylene glycol, acetone, methyl acetate, ethyl acetate, ethylethyl ketone, benzyl alcohol, triacetin, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid and l-dodecylazacycloheptan-2-one. When the SAIB is used as the HVLCM, the preferred solvents are ethanol, dimethylsulfoxide, lactate
P1607 / 97MX of ethyl, ethyl acetate, benzyl alcohol, triacetin, N-methylpyrrolidone, propylene carbonate and glycofurol. The SAIB is not miscible with glycerol, corn oil, peanut oil, 1,2-propanediol, polyethylene glycol (PEG200), super refined sesame oil and super refined peanut oil. Accordingly, this latter group of solvents are not preferred for use with SAIB. Usually, the solvent is added to the compositions in an amount ranging from about 5 percent to about 55 percent by weight, relative to the total weight of the composition. Preferably, the solvent is present in the composition in an amount in the range of from about 10 percent to about 50 weight percent. Another preferred range is from about 10 percent to 30 percent by weight.
V. Uses of LVLCX and HVLCX Compositions. * The composition described in the present can be administered to the host through various methods that can vary depending on the result you want to obtain. When the host is an animal, such as a human, the composition can be administered, for example, topically, systemically (for example, by mucosa (oral, rectal, vaginal or nasal), or parenterally (intravenous, subcutaneous, intramuscular or intraperitoneal)) in a suitable carrier,
P1607 / 97MX if desired. When the composition is used for agricultural pses, it can be applied through irrigation, sprinkling, spray or coating. Preferably, for pharmaceutical or veterinary pses, the compositions herein are administered as solutions by injection or in an aerosol, paste or emulsion. When administered by injection as an LVLCM, the small amount of solvent used in the composition is filtered in the aqueous fluid of the host forming a highly viscous deposit for the controlled release of the substances or a coating for the tissue that can prevent or reduce adhesions. When used in an aerosol or in an emulsion, the small amount of solvent in the solution is evaporated with the application, allowing the LVLCM to establish itself as HVLCM. The formation of aerosols and emulsions can be achieved using techniques known to those skilled in the art. See, for example, Ansel, H.C. et al., Pharmaceutical Dosase Forms and Drus Del 'Systems. sixth edition, 1995. The compositions can be used to form tissue protective coatings, and in particular, they can be used to prevent the formation of surgical adhesions. E-l HVLCM can adhere to the surrounding tissue or bone and can thus be injected via
P1607 / 97MX subdermal as collagen to form tissue or fill defects. It can also be injected into wounds including burn wounds to prevent the formation of deep scars. The degradation time of the HVLCM can be modulated, for example, by using a polymer as an additive to the HVLCM. Afterwards, the implant formed by the HVLCM will slowly biodegrade inside the body and allow the natural tissue to grow and replace the implant when it disappears. In an alternative embodiment, the biologically active substance can be first encapsulated within a microsphere and then incorporated into the invention. In an alternative embodiment, the biologically active substance can be complexed with a complexing agent such as cyclodextrin. In yet another embodiment, the biologically active substance is in the form of a prodrug. "Other means for using this invention include those in which the carrier or controlled release formulation is placed within a gelatin capsule for oral administration, wherein the carrier or controlled release formulation is encapsulated within the microspheres or microcapsules, and preferably wherein the microsphere is a biodegradable polymer such as poly (DL-lactide-co-glycolide);
P1607 / 97MX where the carrier or controlled release formulation is associated with inert pharmaceutical excipients such as microcrystalline cellulose or cellulose acetate, which may optionally then be processed into spheres or other forms and incorporated into a dosage form.
COMPOSITION FOR TOPICAL ORAL ADMINISTRATION A topical oral administration system can be prepared according to this invention so as to contain a surfactant, a cosurfactant, an oily component, a HVLCM, for example, sucrose acetate isobutyrate and water, capable of supporting the supply of the active agent in the oral cavity. The invention can be used, for example, to formulate a long-acting mouthwash containing SAIB and an active agent in a second aqueous-based carrier material in the form of an emulsion. If the mouthwash is used in the conventional way before going to bed, for example, there is a reduction in the alitosis the next morning. The components in the mouthwash formulation can be classified into six groups: antimicrobial actives; surfactants; co-surfactants; oily components; sucrose acetate isobutyrate; water and additives. Each of these groups is explained in more detail below. According to this
P1607 / 97MX description, a person with ordinary experience can prepare other systems for topical oral administration for a wide range of applications, including treatment for oral infections and other oral disorders, by selecting the appropriate active agent. Active Antimicrobial. The antimicrobial active agents that are currently used in mouthwash formulations may include, but are not limited to, domifen bromide, triclosan, chlorhexidine, essential oils, cetyl pyridinium chloride, fluorides, alexidine, salicylanilides, zinc compounds and antibiotics These can be used alone or in combination, cetylpyridinium chloride and zinc compounds, particularly zinc gluconate are preferred. Surfactant In general, the surfactants selected for use in the formulations of the present invention are water soluble and non-ionic, including, but not limited to, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl esters, polyoxyethylene alkyl ethers, polyoxyethylene glycerol esters and sorbitan fatty acid esters, used separately or in combination. The preferred nonionic surfactants are the esters of the polyoxyethylene sorbitan fatty acids with 5-40 moles of
P1607 / 97MX ethylene oxide and polyoxyethylene glyceryl esters with 5-20 moles of ethylene oxide. Particularly preferred are polyoxyethylene sorbitan monooleate (20 O.E.), polyoxyethylene almond oil (20 O.E.), polyoxyethylene hydrogenated castor oil (20 O.E.) and the like. The amount of the surfactant to be incorporated in the formulations of the present invention varies depending on the type of surfactant used. In general, a preferable range is 1-60 weight percent, with particular preference in the range of 2-10 weight percent. Cotensoactivo. In general, the cosurfactant used in the formulations of the present invention is designated as the alcohol or the nonionic component with a low hydrophilic / lipophilic balance (HLB) of the surfactant / co-surfactant system. In the formulation of the present invention, the cosurfactants that have a furcation as * solubilizers or cosoventis are preferred, - "in addition to having function as a surfactant. The monohydric or polyhydric alcohols or the nonionic surfactant with low HLB can be used as a co-surfactant alone or in combinations of two or more of these. Examples of the monohydric alcohols are benzyl alcohol, ethyl alcohol, octyl alcohol and the like; and as examples of polyhydric alcohols are propylene glycol, glycerin, 1,3- P1607 / 97MX butylene glycol and the like. Given as examples of nonionic surfactants with low HLB are the distilled monoglycerides, polyglycerol polyoleates and polyethylene glycols with molecular weights between 300-4,000. Given as more preferred examples of co-surfactants are polyglycerol polyoleates. Included in the particularly preferred co-surfactant are decaglyceryl tetraoleates. The amount of these co-surfactants to be incorporated into the formulations of the present invention varies depending on the type of co-surfactant that is used. In general, a preferable range is 0.5-30% by weight, with a particularly preferable range of 1-5% by weight. Oily Components One or more oily components usually selected from the group consisting of fatty acid esters of glycerin, fatty acid esters, fatty alcohols and their derivatives, benzoates of fatty alcohols and hydrocarbons may be used as the oily component in the formulations of the present invention. The mono-, di- or triglycerides or their acceptable mixtures can be used as the esters of the glycerin fatty acids, regardless of their sources or origins, be they compounds of natural or synthetic origin, or semi-synthetic compounds. The preferred glycerin fatty acid esters are oil of
P1607 / 97MX almond, olive oil, sesame oil, peanut oil, fennel oil, camellia oil, corn oil, castor oil, cottonseed oil and soybean oil, raw or refined, and triglycerides medium chain fatty acids, alone or in combination. The triglycerides of the medium chain fatty acids are particularly preferred. Preferred fatty acid esters are isopropyl myristate, octyl palminate, ethyl oleate, and ethyl palmitate. Particularly preferred are isopropyl myristate and octyl palmitate. Particularly preferred fatty alcohol and benzoate fatty alcohol derivatives are 2-octyldodecanol and C 1 -is alcohol benzoate. Light or heavy liquid lampante oil is mentioned as the preferred hydrocarbon. The oily components can be used alone or in combinations with other oil components. These oily components can be incorporated in the formulations of the present invention in an amount of 0.5-50% by weight and preferably 1-10% by weight. Sucrose isobutyrate acetate. The sucrose acetate isobutyrate described in detail in the foregoing is used as the HVLCM. The SAIB is usually incorporated into the formulation in an amount of 0.01-10%
P1607 / 97MX by weight and preferably 0.1-2% by weight. Water. Another essential component of mouthwash formulations is water. The formulations of the present invention have a pH of 3-10, preferably 5-9, and most preferably 6-8. Buffering agents can be used to maintain the pH in the aforementioned range. Acetic acid, citric acid, phosphoric acid, benzoic acid and / or its salts are mentioned as examples of preferred buffering agents. The pH can be adjusted during manufacture to the preferred range by the addition of suitable acid or base, preferably hydrochloric acid or sodium hydroxide, depending on the adjustment required. It is also preferred that the water be used in the formulations of the present invention as deionized and filtered water. Additives Other components, such as preservatives, - * stabilizers, anti-oxidants, coloring agents, isotonic agents, flavorings, humectants, sequestrants, vitamins and vitamin precursors and the like, can be added as necessary. Preferred examples of preservatives are parabens derivatives with methyl paraben and propyl paraben as the most preferred preservatives. Preferred examples of antioxidants are butylhydroxyanisole,
P1607 / 97MX butylhydroxytoluene, propylgalate, vitamin E acetate and purified hydroquinone with the most preferred antioxidants being vitamin E acetate and butylated hydroxytoluene. The preferred example of the humectant is sorbitol. Preferred examples of flavorings are peppermint oil, spearmint oil, wintergreen oil, menthol and saccharin. Given as a preferred example of sequestrant is citric acid. Topical oral delivery systems can be prepared according to a conventional method, for example, by separately mixing the oil phase and the aqueous phase, and then combining the two phases at elevated temperature. The mixture of the oil and aqueous phases is then mixed thoroughly and cooled to room temperature before packaging.
SAW. Examples Given the description of the present, a person skilled in the art will be able to prepare and use a wide range of HVLCH compositions. It is suggested that all these various modifications fall within the scope of this invention. The following examples, to facilitate the illustration, describe in detail the preparation and use of the SAIB compositions. Other HVLCMS, additives, substrates and solvents can be used in the same or similar way.
P1607 / 97MX To prepare the desired formulations in the examples, the following general procedures were used. The formulations were made in small flask vials of 20 mL and shaken, mixed and / or heated to dissolve the biologically active substance in the SAIB / solvent system. In the examples where the biologically active substance did not dissolve, the formulations were cooled and agitated to obtain the best distribution of the biologically active substance in droplets. The in vitro release of the biologically active compound was determined using the following general procedure. Phosphate buffered saline ("PBS") (10 mL) of pH 7.4 or pH 6.8 was added to a 16 x 12.5 mm test tube. The pH of the PBS, 7.4 or 6.8, was selected based on the application and solubility of the biologically active substance. The PBS included 0.2% sodium azide to prevent the growth of microorganisms. 0.03 to 0.09 grams of the SAIB / Solvent / biologically active substance formulation were deposited from a disposable plastic pipette into the test tube, and the weight was recorded. The test tubes were capped and placed in a stirred bath prepared at 37 ° C with constant agitation. The test tubes were periodically removed
P1607 / 97MX of the bath with stirring at various time points. At this time, the PBS was removed from the test tube with the formulation and placed in a clean, dry test tube. These samples were analyzed at UV to determine the amount of material biologically in the PBS solution. Fresh PBS was placed in the test tube with the formulation, which was then removed from the bath with shaking. This procedure was repeated at different time points for which the samples were obtained. The concentration of the biologically active material in the release solutions was used to construct the release profiles, based on the original amount of the biologically active material in the formulation. This amount was determined using UV-visible spectrophotometry. In these examples various solvents were used, including: ethanol (EtOH), dimethyl sulfoxide (DMSO), ethyl lactate (EtLac), ethyl acetate (EtOAc), benzyl alcohol (FCH20H), triacetin, N-methylpyrrolidone (NMP), carbonate of propylene (PC) and glycofurol (GF). Larger percentages of solvent generally provided a higher concentration of the biologically active substance in the formulation. The amount and type of solvent is also related
P1607 / 97MX directly with the viscosity of the solution. Table 1 shows the effect of the solvent and the concentration in a SAIB / solvent mixture. The viscosity data were obtained using the Cannon-Penske viscometer of size 200 at 30 ° C.
Effect of the Biologically Active Substance To demonstrate the release of the drug, methylene blue and bovine serum albumin (BSA) were used.
The biologically active compounds released from the system included chlorhexidine, diclofenac,
P1607 / 97MX doxycycline, flurbiprofen, naproxen and theophylline. Due to the poor solubility in water the clotrimazole release was not continued.
EXAMPLE 1 Ethanol (1 g.) Was combined with sucrose acetate isobutyrate (SAIB) (9 g.). After mixing gently, a clear solution with low viscosity was obtained. A drop of this solution, with the help of a glass pipette, was deposited in water and formed a spherical matrix that kept its shape for more than a week.
EXAMPLE 2 Ethanol (2 g.) Was combined with SAIB (8 g.). The resulting solution, when mixed with water, formed a thin film. The film kept its shape for more than a week.
EXAMPLE 3 Solutions with different amounts of ethanol and SAIB were prepared according to the process of Example 1. To this solution was added 0.07% methylene blue. Spherical droplets were prepared in phosphate buffered saline (PBS), as described in Example 1. The PBS samples were maintained at 37 ° C. TO
P1607 / 97MX regular intervals the PBS was removed and analyzed for the content of methylene blue by visible-ultraviolet spectrophotometry. The results of the methylene blue release are shown in Figure 1.
EXAMPLE 4 A series of formulations was prepared according to the process of Example 3 using bovine serum albumin (BSA) instead of methylene blue. In these formulations, different percentages of BSA, solvents and SAIB were used. The identity of the solvents and the proportions of BSA, solvent, SAIB and any of the additives are set out below in Tables 2 to 4. The release of BSA was reduced with ever larger proportions of CAP: SAIB. The BSA was not soluble in the system. Attempts were made with mixed solvents to stabilize it, but BSA was only soluble in glycerol and water that are not available with SAIB. All formulations containing BSA in the release profiles were non-homogeneous. Table 2 shows the formulations containing BSA.
P1607 / 97MX TABLE 2
Figure 5 illustrates the release profile for SAIB / BSA pulp that was formed without the use of any additional solvent. A release profile was attempted but was not achieved from the non-homogeneous formulations shown in
P1607 / 97MX Table 4.
TABLE 4
EXAMPLE 5 The procedure of Example 3 was repeated using a series of formulations containing chlorhexidine as the biologically active agent. Formulations with different amounts of solvent, SAIB and additives were prepared. The formulations to which chlorhexidine was added as the biologically active substance are set forth below in Table 7.
P1607 / 97MX TABLE 5
P1607 / 97MX The release profile for chlorhexidine in different solvents is illustrated in Figures 6 to 8. The optimization of the soluble amount of chlorhexidine in SAIB / EtOH / CAB was carried out. The results are shown in Table 6.
EXAMPLE 6 The procedure of Example 3 was repeated using a series of formulations with diclofenac sodium as the biologically active agent. Formulations with different amounts of solvent, SAIB and additives were prepared. The release rate of diclofenac was reduced by increasing the CAB: SAIB ratios. The formulations to which diclofenac was added as the biologically active substance are set forth in Table 7 below.
P1607 / 97MX
607 / 97MC The release profile for diclofenac in different solvents is illustrated in Figures 9 to 12.
The procedure of Example 3 was repeated using a series of formulations with doxycylin as the biologically active agent. Formulations with different amounts of solvent, SAIB and additives were prepared. The formulations to which doxycycline was added as the biologically active substance are set forth below in Table 8.
A small amount of DMSO was used with the nß07 / »7MX combination SAIB / EtOH / CAB to aid in the solubility of doxycycline. These formulations are shown below in Table 9.
EXAMPLE ß The procedure of Example 3 was repeated using a series of formulations with flurbiprofen as the biologically active agent. Formulations with different amounts of solvent, SAIB and additives were prepared. The formulations to which flurbiprofen was added as the biologically active substance are set forth below in Table 10.
TABLE 10% Solvent% additive% additive solvent solubility 2.48 EtOH 15 - - soluble
P1Í07 / 97MX
The release profile for flurbiprofen is shown in Figure 13.
The procedure of Example 3 was repeated using a series of formulations with naproxen (free acid) as the biologically active agent. Formulations with different amounts of solvent, SAIB and additives were prepared. The formulations to which naproxen (free acid) was added as the biologically substantive are set forth below in Table 11.
PlS07 / 97MX SJBHPQ tp The procedure of Example 3 was repeated using a series of formulations with naproxen (sodium salt) as the biologically active agent. Formulations with different amounts of solvent, SAIB and additives were prepared. Naproxen (sodium salt) is not soluble in ETOH and EtOAc. The formulations to which a naproxen (sodium salt) is added as the biologically active substance are set forth below in Table 12.
The release profile of naproxen (free acid and sodium salt) in different solvents is shown in Figure 14.
The procedure of Example 3 was repeated using a series of formulations with naproxen (salt
P1Í07 / 97MX sodium) and naproxen (free acid) as the biologically active agent. Formulations with different amounts of solvent, SAIB and additives were prepared. The formulations to which naproxen (sodium salt) and naproxen (free acid) were added as the biologically active substance are set forth below in Table 13.
--K - C - H? Xa ------------------ Jft? FlL The procedure of Example 3 was repeated using a series of formulations with theophylline as the agent biologically active. Formulations with different amounts of solvent, SAIB and additives were prepared. The formulations to which theophylline was added as the biologically active substance are set forth below in Table 14.
P1607 / 97KX
607 / 97HX
The release profile for theophylline in propylene carbonate is shown in Figure 16. A release profile was attempted in the following formulations with theophylline but the samples were very cloudy. The amounts of materials in these formulations are shown below in Table 15.
P1607 / 97MX EXAMPLE 13 A formulation was prepared with 80% SAIB and 15% ethanol, the resulting solution was loaded into an aerosol container. The solution was sprayed onto agar plates where a continuous adhesive film was formed.
A series of formulations with SAIB was prepared
80%, 0.02% methylene blue and different proportions of ethanol to CAB, from 1: 0 to 1: 1. The formulations were sprinkled in gelatin. The dilution of methylene blue in gelatin was reduced by increasing the CAB content.
GJBUPLO 15 SAIB was heated to 60 ° C. separate formulations were made with 1, 2, 5 and 10% tetracycline. The formulations were loaded into a syringe equipped with a 21-gauge needle. The formulations were manually expelled from the syringe in butter at 37 ° C. The formulations could be easily expelled at temperatures of approximately 45 ° C.
BF-BUMiP ** t PREFA-WCIÓM AND FROPIKDADB »PB EHJU? OUE BUC? L Polyoxyethylene almond oil (7,680 g, 20 E. C.) (Crovol A-70), 4. 042 g of decaglycerol tetraoleate
P1607 / 97MX (Caprol 1OG40) and 11,721 g of medium chain triglyceride (Neobee M-5) were combined in a suitable mixing vessel (kettle with sweeping surface, single action and chamfered). The mixture was heated to about 65 ° C. Methylparaben (0.500 g), 0.250 g of propylparaben, 0.125 g of cetylpyridinium chloride, 0.125 g of benzoic acid and 0.625 g of sucrose acetate isobutyrate were mixed in the heated organic phase. The mixture of the organic phase was maintained at around 65 ° C throughout the addition of the components. Zinc gluconate (0.250 g), 0.125 g of sodium benzoate, 0.0625 g of citric acid and 12.5 g of sorbitol were dissolved in 221.10 g of deionized water. The mixture of the aqueous phase was heated to about 65 ° C. After the mixture of the organic phase and the aqueous phase reached the temperature, the aqueous phase was slowly added to the oil phase with stirring. When the aqueous phase was added completely to the oil phase, two drops of food-grade green dye and 1,000 g of peppermint oil were added and mixed perfectly in the formulation. The mixture was then cooled rapidly to room temperature and packed. The loss of water during processing on this scale is about 10. l g. The finished product had the following composition. P1607 / 97MX
A vascular graft was submitted in a solution of SAIB to 61.8%, CAB 10.0% and ETOH 28.2% to which was added
P1607 / 97HX 1% heparin. The graft was drained from the solution and rinsed with physiological saline. After the explanation, the internal surface of the graft was free of coagulated blood compared to a control vascular graft.
Formulations of 5% CAB, 45% ethanol and 50% SAIB were prepared. To these was added transforming beta growth factor in amounts from 0.05-0.0005%, or phenol in a range of 1-5.1%. The compositions were injected into the inguinal canal of a dog where they produced a cellular response that gave rise to the occlusion of the canal.
fiJgHFt-o 19 Formulations of CAB 10%, ethanol 45% and SAIB 45% were sprayed into the uterine tube of a rabbit, which had been surgically abradiated. The areas not all showed the elimination of the surgical adherence when they were reexamined, nevertheless the article was well tolerated biologically.
E-Z-BSI-SL-I? Figure 17 is a graph of the release of two formulations. A formulation (dark shading)
P1Í07 / 7MX contains SAIB 3.2%, ETOH 15.1%, methylene blue 0.00395% and the remainder diH20. The other formulation (inclined shading) was SAIB 0%, ETOH 28.9%, methylene blue 0.00395% and diH20. One-inch natural collagen strips were cut, rinsed in PBS (pH 6.8), immersed in the formulation for nine minutes, placed in clean test tubes and covered with PBS. At different time points the PBS was decanted and analyzed under UV; fresh PBS was added to the test tubes with collagen. See Figure 17. Modifications and variations of the present invention, compositions and methods of use thereof, will be obvious to those skilled in the art from the detailed description mentioned above. These modifications and variations are proposed to be within the scope of the appended claims.
P1607 / 97MX
Claims (45)
- Having described the present invention, it is considered as a novelty and, therefore, the content of the following SR? ViNDTC joires is claimed as property: 1. A composition for the controlled release of biologically active substances that contains: (a) a liquid carrier material, insoluble in water, non-polymeric, having a viscosity of at least 5,000 cP at 37 ° C, which does not crystallize pure under environmental or physiological conditions; and (b) a biologically active substance. The composition of claim 1, wherein the water-insoluble liquid carrier material is sucrose diacetate hexaisobutyrate. The composition of claim 2, wherein the water-insoluble liquid carrier material is present in an amount from about 99.5 percent to about 10 weight percent relative to the total weight of the composition. The composition of claim 3, wherein the water-insoluble liquid carrier material is present in an amount from about 99.5 percent to about 0.20 percent by weight relative to weight P1607 / 97HJT total composition. The composition of claim 2, wherein the composition further contains a solvent in which the liquid carrier insoluble in water is soluble. The composition of claim 5, wherein the solvent is selected from the group consisting of ethanol, dimethyl sulfoxide, ethyl lactate, ethyl acetate, benzyl alcohol, triacetin, N-methylpyrrolidone, propylene carbonate, and glycofurol. The composition of claim 5, wherein the solvent is present in an amount from about 10 to about 50 weight percent, based on the weight of the composition. The composition of claim 2, wherein the composition further contains an additive. 9. The composition of claim, wherein the additive is selected from biodegradable polymers, non-biodegradable polymers, natural oils, synthetic oils, carbohydrates, carbohydrate derivatives, inorganic salts and inert organic compounds. The composition of claim 8, wherein the additive is present in an amount in the range of from about 1 to about 20 weight percent, relative to the total weight of the composition. ll. The composition of claim 2, in P1607 / 97WX wherein the biologically active substance is selected from the group consisting of drugs, peptides, proteins, nucleoproteins, ucoproteins, lipoproteins, polysaccharides and their derivatives, heparin, polypeptides or synthetic proteins or a small molecule bound to a protein, glycoproteins, steroids , nucleic acid or a fragment thereof, nucleotide, nucleoside, oligonucleotides, genes, lipids, hormones, vitamins. 12. An emulsion for the controlled release of biologically active substances that includes: (a) a water-insoluble, non-polymeric liquid carrier material having a viscosity of at least 5,000 cP to 37ßc that does not crystallize pure under environmental or physiological conditions; and (b) a biologically active substance in an aqueous-based carrier. A method for administering the controlled release composition of claim 1, comprising the step of administering the composition to the host in an emulsion or in a solution. A method for the administration of the controlled release composition of claim 1, comprising the step of administering the composition to the host by injection. 15. A method for the administration of -P1-S07 / 97MX controlled release composition of claim 1 comprising the step of administering the composition to the host through aerosol. 16. The controlled release formulation of claim 1 for use in veterinary therapy. 17. The controlled release formulation of claim 1 for use in agricultural products. 18. The controlled release formulation of claim 1 for use in human therapy. 19. The controlled release formulation of claim 1 for use for blocking surgical adhesions. 20. The controlled release formulation of claim 1 for use for blocking surgical adhesions. 21. The controlled release formulation of claim 1 for use in scaffolding, filling of holes or tissue regeneration. 22. The controlled release formulation of claim 1 for use to block the arterial supply of the tumor. 23. The controlled release formulation of claim 1 for use as a tissue adhesive. 24. The controlled release formulation of claim 1 for use in wound healing. P1607 / 97MX 25. The carrier material of claim 1 for use in veterinary therapy. 26. The carrier material of claim 1 for use in agricultural products. 27. The carrier material of claim 1 for use in human therapy. 28. The carrier material of claim 1 for use for blocking surgical adhesions. 29. The carrier material of claim 1 for use for blocking surgical adhesions. 30. The carrier material of claim 1 for use in scaffolding, gap filling or tissue regeneration. 31. The carrier material of claim 1 for use for blocking the arterial supply of the tumor. 32. The carrier material of claim 1 for use as a tissue adhesive. 33. The carrier material of claim 1 for use in healing wounds. 34. The controlled release material of claim 1 in the form of an emulsion for use as a mouthwash. 35. The composition of claim 1, wherein the biologically active molecule is heparin. 36. The composition of claim 1, in P1-S07 / 97MX where the carrier is disaccharide butyrate acetate. 37. The composition of claim 1, wherein the carrier is a disaccharide ester. 38. The composition of claim 1, wherein the biologically active substance is first encapsulated within a microsphere and then incorporated into the carrier material. 39. The composition of claim 1, wherein the biologically active substance can be complexed with a complexing agent such as cyclodextrin. 40. The composition of claim 1, wherein the biologically active substance is in the form of a prodrug. 41. The composition of claim 1, wherein the controlled release formulation is placed within a gelatin capsule for oral administration. 42. The composition of claim 1, wherein the controlled release formulation is encapsulated within a microsphere or microcapsule. 43. The composition of claim 42, wherein the microsphere is a biodegradable polymer. 44. The composition of claim 43, wherein the polymer is poly (DL-lactide-co-glycolide). 45. The composition of claim 1, wherein the controlled release formulation is associated with P1607 / 97MX inert pharmaceutical excipients such as microcrystalline cellulose or cellulose acetate which may optionally then be processed into spheres or other forms and incorporated into a dosage form. P1607 / 97MX RBffvHBW Pi LA jwymciOif The present invention relates to a composition for the controlled release of a substance that includes: (i) a liquid, water-insoluble, non-polymeric carrier material (HVLCM) of viscosity of at least 5,000 cP at 37 ° C, which does not crystallize under environmental or physiological conditions; and (ii) a substance to be released. Plß07 / 97MX
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US47845095A | 1995-06-07 | 1995-06-07 | |
US08/478,450 | 1995-06-07 | ||
US08474337 | 1995-06-07 | ||
US08/474,337 US5747058A (en) | 1995-06-07 | 1995-06-07 | High viscosity liquid controlled delivery system |
Publications (2)
Publication Number | Publication Date |
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MX9709606A MX9709606A (en) | 1998-06-30 |
MXPA97009606A true MXPA97009606A (en) | 1998-10-30 |
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