NZ203594A

NZ203594A - Biosoluble ocular insert

Info

Publication number: NZ203594A
Application number: NZ20359483A
Authority: NZ
Inventors: J V Bondi; R J Harwood
Original assignee: Merck & Co Inc
Priority date: 1983-03-16
Filing date: 1983-03-16
Publication date: 1986-02-21

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £03594 2 035 M I A ( . ,<r //V i, \o ■ Priority Date(s); Complete Specification Filed: Class: HV) I /tv3 i&Qs c^o3;-5) ]Oj^ Publication Date: ft.1.FE-B• 1986 P.O. Journal, No: A^f;' <0 2 1 FEB 1986 Dais NEW ZEALAND PATENTS ACT. 1953 COMPLETE SPECIFICATION BIOSOLUBLE OCULAR INSERT X/We, MERCK & CO., INC., a corporation organized under the laws of the State of New Jersey, United States of America, of Rahway, New Jersey, United States of America. hereby declare the invention for which 5 / we pray that a patent may be granted to tor/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (followed by la) \ 203594 - - - lo- 1 WOtj. TITLE OF THE INVENTION BIOSOLUBLE OCULAR INSERT BACKGROUND OF THE INVENTION: 5 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 olurred vision and which when formulated with enteric 10 coating materials as a constituent of the matrix provide a means for controlling and predicting dissolution rates for slow release and prolonged therapeutic ef fect. Solid ocular inserts are now well known in 15 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 20 altered the viscosity and refractive index of the tear film. These changes resulted in the formation of "Schlieren" or discontinuities in the 2 035 9 - 2 - MB 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 5 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 10 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 15 gelatinous masses in the cul-de-sac. DESCRIPTION OF THE INVENTION The novel non-vision blurring ocular insert of this invention comprises a number of different 20 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 25 desired shape and integrity. The particular polyvinyl alcohol useful in the novel insert has a molecular weight between about 2000 and 3000 and forms about 0% to about 100% by weight of the finished product. 30 Plasticizer: The ocular inserts prepared in accordance with this invention may also contain plasti-cizersto 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%. Hvdroxvpropvl 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 inaomethacin 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 203594 - 4 - distributed therein. It constitutes up to about 99% 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-Phramacologicallv 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 physiologically 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, genta-mycin, 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- 2 ZBwn 5 esses? amine and prophenpyridamine; steroidal antiinflammatories such as hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrvsone, prednisolone, methylpredni-solone, 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-isopropvl fluorophosphate, phospholine iodide, and demecarium bromide; mydriatics such as atropine sulfate, cyclopentolate homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine; sympathomimetics such as epinephrine; and p-blockers such as propanolol and timolol. different forms, such as uncharged molecules, components of molecular complexes or non-irritating, pharmacologically acceptable derivatives thereof. Simple derivatives of the drugs such as pharmaceutical^ 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. 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 Drugs contained in the insert can be in The amount of drug incorporated in the o £* V.; « ' > ;- 6 - J3PHR ;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 thera-5 peutically 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 10 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. 15 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 20 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 25 of the polymer(s) described above. For example, the medicament and the polymer(s) can be warmed together at temperatures between about 150°F and 400°F and the resulting mixture compression molded to form a thin film. it is generally preferred to prepare the 30 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, ;- 7 - ;iff my 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 5 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. 10 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 15 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. ;20 ;25 ;30 ;203594 ;- 8 - ;EXAMPLE 1 ;The following table exemplifies 7 typical formulations with their respective dissolution times. ;Composition of S«ven Ophthalmic insert Matrices ;Hg. pec 3 Insect ;CooposIt ion A B C D ;Polyvinyl Alcohol 1.50 0.45 1.SO 2.10 Hyd roxypropyl cellulose EF 0.60 - - - 0,60 Hydroxypropyl aethylcellulose phthalate - 2.25 - - 1.35 ;Polyvinylpyrrolidone - - 0.60 - - ;Mannitol 0.75 - 0.75 0.75 - - 0.55 ;Clycerin 0.15 0.30 0.15 0.15 0.15 - 0,15 ;Timolol saleate - - - 0.20 ;Est iraated d i ssolut ion time in v i vo baaed on 15 siin. 6-7 hrs. 15 sin. 15 «in. 1-2 hrs. 30 roin 15 si in vitro and in vivo data in raooits ;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 lengths of the desired size. ;Hydroxypropyl cellulose EF is an hydroxypropyl cellulose characterised in that a 10% aqueous solution has a viscosity of 300-700 cps and the polymer has an average m.w. of 60,000. ;203594 ;- 9 - ;EXAMPLE 2 Assay of Vision Blurring Potential ;An i_n 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 comoosition is tested in 3 animals. ;RESULTS ;Insert ;Distortion Index ;Duration of ;Distortion ;5 ;mg ;Hydroxypropyl cellulose HF ;415 ;120 ;min. ;3 ;mg ;Hydroxypropyl cellulose GF ;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. ;Hydroxypropyl cellulose HF is an hydroxypropyl cellulose characterised in that a 1% solution has a viscosity of 15 0 0-250 0 cps and the polymer has an average m.w. of 1 x 106. * </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 2.03594 - 10 - Hydroxypropyl cellulose GF is an hydroxypropyl cellulose characterised in that a 2% solution has a viscosity of 150-400 cps and the polymer has an average m.w. of 300,000. - 11 - 203594 WHAT WE CLAIM IS:

1. A non-vision-blurring ocular insert comprising the following components: 5 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 10 30,000-100,000; d) 0-20% by weight of polyvinylpyrrolidone ; e) 0-30% by weight of a monosaccharide alcohol; 15 f) 0-99% 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^ with the proviso that the components a) through g) are present in a total of 100 percentage parts by weight.

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 hydroxy- 25 propylmethylcellulose phthalate.

3. The formulation of Claim 1 or 2 wherein the components a) through g) are present in the following percentage parts by weight: 30 a) 50%; b) 5%; c) 20%; d) 0% ; e) 25%; f) 0%; g) 0%.

■V o\ 4. The formulation of Claim 1 or 2 wherein the components a) through g) are present in the 26NOVi985 follow ing percentage parts by weight: "3 § 8 203594 - 12 - a) 15%; b) 10%; c) 0%; d) 0%; e) 0% f) 75%; g) 0%.

5. The formulation of Claim 1 or 2 wherein 5 the components a) through g) are present in the following percentage parts by weight: a) 50%; b) 5%; c) 0%; d) 20%; e) 25%; f) 0%; g) 0%. 10

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 hydroxvpropylcellulose EF (as hereinbefore defined), 0.75 mg of mannitol and 0.15 mg 15 of glycerin.

7. The non-vision-blurring ocular insert formulation of Claim 1 or 2 which weighs aporoxi-matelv 3 mg and is composed of 0.45 mg of polyvinyl alcohol, 2.25 mg of hydroxypropylmethvlcellulose 20 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 1.5 mg of polyvinvl 25 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- 30 o\ '<* V1 . i; MCV !98S"l) 13 mately 3 mg and is composed of 2.10 mg of polyvinvl alcohol, 0.75 mg of mannitol and 0.15 mg of glycerin.

10. The non-vision-blurring ocular insert 5 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. in OATtD THtt /{& DM A. J. PARK fc SON tu ^ AGINT1 fO* TM AffltCANTI 15 20 ■f ■,o* 25 30 y-. </div>