BIOSOLUBLE OCULAR INSERT

Abstract: Ocular inserts with or without pharmacologically active agents comprising low molecular weight polymers do not cause blurred vision. When an enteric coating material is included as a constituent of the matrix there is provided a means for controlling and predicting dissolution rates of the insert to yield a prolonged therapeutic effect.

Description: TITLE OF THE INVENTION BIOSOLUBLE OCULAR INSERT BACKGROUND OF THE INVENTION: This invention is concerned with novel ocular inserts, with or without a pharmacologically active agent, comprising low molecular weight polymers including polyvinyl alcohol which do not cause blurred vision and which when formulated with enteric coating materials as a constituent of the matrix provide a means for controlling and predicting dissolution rates for slow release and prolonged therapeutic effect. Solid ocular inserts are now well known in the art and they are generally a great advance over the prior liquid and ointment forms of medication. However, the prior art solid biosoluble ocular inserts frequently caused blurred vision because the high molecular weight polymers commonly employed altered the viscosity and refractive index of the tear film. These changes resulted in the formation of "Schlieren" or discontinuities in the precorneal tear film. The prior art solid biosoluble inserts also served to augment the blurring by the presence of a large volume of the gelatinized, hydrated polymers which tended to fracture into fragments due to blinking, giving rise to a potentially more rapid dissolution. Now with the present invention there is provided ocular inserts that minimize the blurred vision effect by providing materials that do not materially change the viscosity and index of refraction of the tear film and optionally provide those materials at a rate sufficiently slowly as to provide only low volumes of the solubilized polymers In addition, the compositions described do not form gelatinous masses in the cul-de-sa. DESCRIPTION OF THE INVENTION The novel non-vision blurring ocular insert of this invention comprises a number of different components in various relative amounts and may or may not include a pharmacologically active agent. These components are: Polyvinyl Alcohol: This component is one of the principal matrix materials giving the insert its desired shape and integrity. The particular polyvinyl alcohol useful in the novel insert has a molecular weight between about 20QO and 3000 and forms about 0% to about 100% by weight of the finished product. Plasticizer: The ocular inserts prepared in accordance with this invention may also contain plasti cizers-to make the ophthalmic inserts more pliable. Plasticizers suitable for this purpose must, of course, also be completely soluble in the lacrimal fluids of the eye. Examples of suitable plasticizers are water, polyethylene glycol, propylene glycol, glycerine, trimethylol propane, di- and tripropylene glycol, hydroxypropylsucrose and the like. Typically, such plasticizers can be present in the ophthalmic insert in an amount ranging from about 0% to about 30% by weight. A particularly preferred plasticizer is glycerin which is present in amounts of at least about 1.0% up to about 10%. Hydroxypropyl cellulose: The hydroxypropyl cellulose useful in the formulation of this invention is of low molecular weight from about 30,000 to about 100,000. It is an optional component and is present in amounts from 0-50% by weight of the finished insert. Polyvinylpyrrolidone: Polyvinylpyrrolidone is an optional component present in amounts from 0 to about 20% by weight and its presence or absence is dictated by the nature of the pharmacologically active agent tnat may be included. It complexes with certain materials such as indomethacin and is known to bind with certain tissue and thus has the potential of creating a depot type of medication. Monosaccharide alcohol: Mannitol, sorbitol, or any of the other sugar alcohols, but especially mannitol, optionally may be included as a component of the insert as a diluent up to about 30% by weight of the total. Enteric Coating Polymer: An optional component is one of the several known enteric coating polymers such as hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethyl cellulose acid succinate, or acrylic acid polymer, which is not present as a coating, but rather as a component of the matrix, being homogeneously distributed therein. It constitutes up to about 100% by weight of the total and serves to provide a slow even release of pharmacologically active agent or a slow-release source of the polymer itself or the other components such as polyvinyl alcohol and hydroxypropylmethylcellulose. Incorporation of one of the enteric coating materials extends the dissolution rate from about 15 minutes up to about 24 hours, depending on the relative amount of the material. Phramacologically active Agent: If the novel ocular insert of this invention is intended for delivery of a pharmacologically active agent it is incorporated therein in an amount up to about 99% by weight thereof. Suitable drugs for use-in therapy with the ocular drug delivery system of the invention include, without limitation, drugs that produce a physiolog-ically or pharmacologically localized or systemic effect in animals, including warm blooded mammals, human and primates, valuable domestic household, sport or farm animals such as horses, dogs, cats, cattle, sheep and the like; or for administering to laboratory animals such as mice, monkeys, rats, rabbits and guinea pigs. The active drugs that can be administered by the novel drug delivery system of the invention include, without limitation: antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, gentamycin, and erythromycin; antibacterials such as sulfonamides, sulfacetamide, sulfamethizole and sulf isoxazole; antivirals, including idoxuridine; and other antibacterial agents such as nitrofurazone and sodium propionate; anti-allergenics such as antazoline, methapyriline, chlorpheniramine, pyril amine and prophenpyridamine; steroidal antiinflammatories such as hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrysone, prednisolone, methylprednisolone, prednisolone 21-phosphate, prednisonolone acetate, fluoromethalone, betamethasone and triamcinolone; non-steroidal anti-inflammatories such as indomethacin, sulindac and aspirin; decongestants such as phenylephrine, naphazoline, and tetrahydrazoline; miotics and anticholinesterases such as pilocarpine, eserine, carbachol, di-isopropyl fluorophosphate, phospholine iodide, and demecarium bromide; mydriatics such as atropine sulfate, cyclopentolate homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine; sympathomimetics such as epinephrine; and B-blockers such as propanolol and timolol. Drugs contained in the insert can be in different forms, such as uncharged molecules, components of molecular complexes or non-irritating, pharmacologically acceptable derivatives thereof. Simple derivatives of the drugs such as pharmaceutically acceptable ethers, esters, amides, and the like which have desirable retention and release characteristics but which are easily hydrolyzed by body pH, or enzymes to active forms, and the like, can be employed. The amount of drug incorporated in the system varies depending on the drug, the desired therapeutic effect, and the time span for which the system provides therapy. Since a variety of systems in a variety of sizes and shapes are intended to provide dosage regimens for therapy for a variety of maladies, there is no critical upper limit on the amount of drug incorporated in the system. The lower limit too will depend on the activity of the drug and the time span of its release from the system. Thus, it is not practical to define a range for the therapeutically effective amount of drug to be incorporated in or released by the system. However, the amount of drug present is generally nonlimited and it is an amount equal to or larger than the amount of drug that on its release from the system is effective for bringing about the drug's effects. Generally, an ocular system containing a pharamacologically active agent will contain from 1 microgram to about 300 micrograms of drug or more, for releasing the drug to the eye at art recognized dosage rates. The compositions of this invention can be prepared by various methods. Thus, the drug and the polymer(s) can be dissolved in a suitable solvent and the solution evaporated to afford a thin film comprising the polymer(s) and the drug which can then be subdivided to prepare suitable inserts containing the desired amount of the medicament. Alternatively, and in accordance with a preferred embodiment of our invention, we find that the inserts can be prepared most conveniently using the thermoplastic properties of the polymer(s} described above. For example, the medicament and the polymer(s) can be warmed together at temperatures between about 1500F and 4000F and the resulting mixture compression molded to form a thin film. It is generally preferred to prepare the inserts by compression molding or extrusion in accordance with procedures which are well known in the art. The compression molded or extruded product can then be subdivided to afford inserts of suitable size for administration in the eye. For example, castings or compression molded films having a thickness of about 0.5 mm. to 1.5 mm. can be subdivided to obtain suitable inserts in the form of squares, rectangles, circles, semi-circles, and the like containing the desired amount of active ingredient. Rectangular segments of the cast or compressed film having a thickness between about 0.5 and 1.5 mm. can be cut to afford shapes such as rectangular plates of 4 X 5-15 mm. or ovals of comparable size. Similarly, extruded rods having a diameter between about 0.5 and 1.5 mm. can be cut into suitable sections to provide the desired dosage of medicament. For example, rods of 1.0 to 1.5 mm. in diameter and up to 5 mm. long are found to be satisfactory. The inserts may also be directly formed by injection molding. All of the ophthalmic inserts prepared in accordance with the present invention should be formed so that they do not have any sharp edges or corners which could cause damage to the eye. EXAMPLE 1 The following table exemplifies 7 typical formulations with their respective dissolution times. Coiposition of Seven Ophthalmic Insert Matrixes ng. per 3 pg. Insert Co. osition A B C D E F G Polyvinyl Alcohol TW 0.45 1.50 2.10 1.50 3.0 1.5 Bydroxypropyl cellulose EF 0.60 - - - - - 0.60 Bydroxypropyl methylcellulose phtbalate - 2.25 - - 1.35 - Polyvinylpyrrolidone - - 0.60 - - - Mannitol 0.75 - 0.75 0.75 - - 0.55 Glycerin 0.15 0.30 0.15 0.15 o.1S - 0.15 Timolol maleate - - - - - 0.20 Estimated dissolution time in vivo based on 15 sin. 6-7 hrs. 15 sin. 15 sin. 1-2 hrs. 30 min 15 mi in vitro and in viva data in rabbits Formulation A is prepared as follows: Glycerin and mannitol are blended together to form a granular mass. Polyvinyl alcohol is gradually added until a uniform mixture is obtained. Finally, the hydroxypropyl cellulose is added and the entire mixture extruded using a twin screw extruder to form a strand 1 mm in diameter which can be cut into EXAMPLE 2 Assay of Vision Blurring Potential An in vivo assessment of the blurred vision potential is made using dogs. An insert is placed into the cul-de-sac of a conditioned female beagle dog. Observations of the keratoscopic mires using a self illuminated placido disk (Klein Keratoscope) are then made at regular intervals until the insert is completely dissolved. The degree of distortion of the mires is graded on a scale of one to six. A plot of degree of distortion versus time is made and the area under the curve measured. This value is termed the distortion index. A second value obtained from the measurement is the duration of distortion which is defined as the total time that distortion occurs during a given experiment. For purposes of accuracy, each insert composition is tested in 3 animals. RESULTS Duration Distortion of Insert Index Distortion 5 mg Hydroxypropyl cellulose HF 415 120 min. 3 mg Hydroxypropyl cellulose JF 30 30 min. 5 mg Polyvinyl alcohol 30-20 120 120 min. 2.5 mg Hydroxypropyl cellulose EF 297 180 min. Matrix A of Example 1 5 10 min. B of Example 1 0 0 min. C of Example 1 0 0 min. D of Example 1 8 10 min. E of Example 1 2 5 min. F of Example 1 18 15 min.

Claims: WHAT IS CLAIMED IS: 1. A non-vision-blurring ocular insert comprising the following components: a) 0-100% by weight of polyvinyl alcohol with a molecular weight of 2000-3000; b) 0-30% by weight of plasticizer; c) 0 50% by weight of hydroxypropyl cellulose with a molecular weight of 30,000-100,000; d) 0-20% by weight of polyvinyl pyrrolidone; e) 0-30% by weight of a monosaccharide alcohol; f) 0-100% by weight of an enteric coating; polymer homogeneously distributed within the matrix of the insert; and g) 0-99% by weight of a pharmacologically active agent. 2. The formulation of Claim 1, wherein the plasticizer (component b) is glycerin; the monosaccharide alcohol (component e) is mannitol; and the enteric coating polymer (component f) is hydroxypropylmethylcellulose phthalate. 3. The formulation of Claim 1 or 2 wherein the components a) through g) are present in the following percentage parts by weight: a) 50%; b) 5%; c) 20*; d) 0%; e) 25%; f) 0%; g) 0%. 4. The formulation of Claim 1 or 2 wherein the components a) through g) are present in the following percentage parts by weight: a) 15%; b) 108; c) 0%; d) 0*; e) 0% f) 758; g) 08. 5. The formulation of Claim 1 or 2 wherein the components a) through g) are present in the following percentage parts by weight: a) 508; b) 5*; c) 0%; d) 20%; e) 25%; f) 0%; g) 0%. 6. The non-vision-blurring ocular insert formulation of Claim 1 or 2 which weighs approximately 3 mg. and is composed of 1.50 mg of polyvinvl alcohol, 0.6 mg of hydroxypropylcellulose EF, 0.75 mq of mannitol, and 0.15 mg of glycerin. 7. The non-vision-blurring ocular insert formulation of Claim 1 or 2 which weighs apDroxi- mately 3 mg and is composed of 0.45 mg of polyvinyl alcohol, 2.25 mg of hydroxypropylmethvlcellulose phthalate, and 0.30 mg of glycerin. 8. The non-vision-blurring ocular insert formulation of Claim 1 or 2 which weighs approximately 3 mq and is composed of l.5.mg of polyvinyl alcohol, 0.60 mg of polyvinylpyrrolidone, 0.75 mg of mannitol and 0.15 mg of glycerin. 9. The non-vision-blurring ocular insert formulation of Claim 1 or 2 which weighs approxi mately 3 mg and is composed of 2.10 mg of polyvinyl alcohol, 0.75 mg of mannitol and 0.15 mg of glycerin. 10. The non-vision-blurring ocular insert formulation of Claim 1 or 2 which weiqhs approximately 3 mg and is composed of 1.50 mg of polyvinyl alcohol, 1.35 mg of hydroxypropylmethylcellulose, and 0.15 mg of glycerin.

Inventors: HARWOOD, RICHARD J., V. BONDI, JOSEPH
Applicants: MERCK & CO. INC.
Application year: 1982
Main classification: A61K9
IPC codes: A61K9, A61F9