FI58433B - PREPARATION OF THE PREPARATION OF THE PREPARATION - Google Patents

Abstract

The ophthalmic inserts containing hydroxypropylcellulose as carrier material are particularly effective because they dissolve slowly but completely in water so that they can be used for the production of suitable compositions for prolonged treatment of the eye with, at the same time, a reduction in the dosage frequency.

Description

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(32) (33) (31) Pyr ^ * «jr ncuolknu * —a ^ w pHorlttt ιγ'12.73 31.10.jb USA 425 ^ 26, 519323 (71) Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey, USA (72) Edward Morton Cohen, Norristown, Penn., Wayne Martin Grim, Doyles-town, Penn., Richard James Harwood, Philadelphia, Penn., USA (US),

Gunvant Nathubhai Mehta, .Bombay, India-Indien (lN) (7¼) Oy Kolster Ab (5¼) Method for the preparation of an ophthalmic preparation - Förfarande för fram-ställning av ett ophthalmiskt preparat

The invention relates to a method for preparing an ophthalmic preparation. The ophthalmic preparation according to the invention is suitable for use in animals and humans. The invention relates in particular to the preparation of therapeutically active substances and solid unit dosage forms of hydroxypropylcellulose which can be used in the treatment of the eye with minimal visual impairment.

Conventional treatment of various ocular ailments involves the administration to the eye of suitable drugs in aqueous suspension solutions or ointments. Although such treatments are satisfactory for the treatment of ocular disorders in cases where the drug is used only once or several times, some ocular disorders require multiple doses and the treatment is uncomfortable for the patient. Recently, the administration of ophthalmically active drugs in solid form in an inert matrix has been proposed (see, for example, U.S. Patent No. 5,710,395 to 5,710,795). This method has the disadvantage that the inert matrix must be removed after the drug has been completely released from the matrix. Recently, Lucoas et al. £). of Pharm. Sci ,,

Butter. 61, page 9 85 (July 1972). found that the alginic acid salt of p iocarpi i n, used as an ophthalmic solid insert, causes a greater blackout-reducing reaction than could be achieved by administering conventional pilo-carpine solutions to the rabbit eye.

The ophthalmic preparation according to the invention has a prolonged activity and a smaller number of doses necessary for the treatment of various eye disorders.

The invention is characterized in that a mixture of 0.1 to 35% of ophthalmically active drug from 65 to 99.9% of hydroxypropylcellulose and 0 to 30% of plasticizer is formed in a manner known per se, for example by molding or injection or extrusion, into a film or rod, having a thickness of 0.5 to 1.5 mm, respectively.

Hydroxypropylcellulose is a non-ionizable, water-soluble 1Slose ether with properties which are excellent for use in the manufacture of ophthalmic preparations. Due to its water solubility, it is soluble in aqueous tear fluids. In addition, it is thermoplastic and can therefore be advantageously combined with an ophthalmic drug using conventional plastic treatment methods, such as injection molding or injection or extrusion, before dividing into unit doses. Hydroxypropylcellulose is available in a variety of polymeric forms, all of which are suitable for the preparation of the ophthalmic preparations of the present invention. Products sold under the tradename Hercules Incorporated of Wilmington, Delaware under the name KLUCEL, such as KLUCEL HF, HWF, MF, GF, 3F, LF and EF, for food or pharmaceutical use are particularly useful in the preparation of the novel formulations of the invention.

The present compositions can be prepared by various methods. The drug and hydroxypropylcellulose can be dissolved in a suitable solvent and the solvent evaporated to give a thin film containing hydroxypropylcellulose and drug, which can then be partitioned to make suitable inserts containing 58433 of the desired amount of drug. Alternatively, and in accordance with a preferred embodiment of the invention, it has been found that the inserts can be conveniently prepared by taking advantage of the thermoplastic properties of hydroxypropylcellulose. For example, the drug and hydroxypropylcellulose a can be heated together to a temperature of about 65-204 ° C and the resulting mixture formed into a thin film. In general, it is preferred to make the inserts by molding or extrusion according to methods well known in the art. The molded or extruded product can then be divided to obtain appropriately sized inserts for ocular administration. For example, castings or molded films having a thickness of about 0.5 to 1.5 mm can be divided into portions to obtain suitable inserts in the form of squares, rectangles, circles, semicircles and the like, which contain the desired amount of active substance. Rectangular segments of a cast or pressed film having a thickness of about 0.5 to 1.5 mm can be cut to obtain rectangular plates or similar ovals having dimensions of 4x5-15 mm. Likewise, extruded rods having a diameter of about 0.5 to 1.5 mm can be cut into suitable sections to obtain the desired dose of drug. For example, rods with a diameter of 1.0 to 1.5 mm and a length of about 10 mm have been found to be satisfactory. The preparations can also be formed directly by injection molding. All eye care inserts made in accordance with the present invention should be formed so that they do not have any sharp edges or angles that could damage the eye.

The ophthalmic inserts made in accordance with this invention may also contain a plasticizer to make the ophthalmic preparation more flexible. Plasticizers suitable for this purpose must, of course, also be completely soluble in the tear fluids of the eye. Examples of suitable plasticizers include water, polyethylene glycol, propylene glycol, glycerin, trimethylolpropane, di- and tripropylene glycol, hydroxypropyl sucrose and the like. Such plasticizers may typically be present in the ophthalmic insert in an amount of about 0-30% by weight. A particularly preferred plasticizer is water present in an amount of at least about 5% and most preferably at least 10%. In practice, a water content of about 10% to 20% is preferred because it can be easily achieved and give the 58433 the desired softness and flexibility.

When softening a solid drug product with water, the drug product is contacted with air having a relative humidity of at least about 40% until said product absorbs at least about 5% water and becomes softer and more flexible. In a preferred embodiment, the relative humidity of the air is about 60% to 99% and the contact is continued until the product has about 10% to 20% water.

Suitable drugs that can be included in the present preparations include antibacterial agents such as β-lactam antibiotics, tetracyclines, chloramphenicol, neomycin, gramisidine, bacitracin, sulfonamides, gentamicin, kanomycin, nitroturazones and the like; antihistamines as well as congestion reducing agents such as pyrilamine, chlorotheniramine, tetrahydrazoline, anthazoline and the like; anti-inflammatory agents such as cortisone, hydrocortisone, β-methazone, dexamethasone, corticolone, prednisone, triamcinolone, indomethacin and the like; blackhead reducing agents and anticholinesterases such as ecothiopathy, pilocarpine, thysostigmine salicylate, diisopropyl fluorostostat and the like; blackhead dilators such as atropine, homatropine, scopolamine, hydroxyamphetamine and the like; and other medicines used to treat eye problems.

These drugs or their derivatives, such as salts, covalent derivatives, for example esters or amides, or other therapeutically active forms, can be mixed with hydroxypropylcellulose in the form of water-soluble inserts prepared as described above for the treatment of various ocular diseases. These forms are particularly advantageous for the treatment of conditions involving long-term administration of the drug, for example in eye diseases or eye disorders such as uveitis, glaucoma, corneal diseases such as purulent keratitis, herpes simplex keratitis, herpes zoster, acne rosacea, varus-tissue similar, ocular diseases such as exophthalmos and periostitis, and conjunctival diseases such as mucus-wet conjunctivitis and ophthalmia.

5,58433 A method of administering drugs as a water-soluble insert is particularly useful for administering pilocarpine for the treatment of glaucoma, a disease characterized by an increase in intraocular pressure. Current treatment for this disease involves the use of solutions of pilocarpic acid salts which are applied to the eye in the form of drops at frequent intervals. When the ocular inserts of the present invention are applied to the eye, a 9-10 hour ophthalmic astringent effect can be achieved in rabbits, while a short duration of 2-4 hours is achieved when the drops are administered. Pilocarpine may preferably be administered in the form of acid salts of this drug, such as hydrochloride, alginate, pamoate and the like. The ophthalmic inserts of the present invention may contain up to about 35% by weight of pilocarp to provide a dose of about 1 to 6 mg of pilocarpine per insert.

The ophthalmic inserts of the present invention generally contain from about 0.1% to about 35% drug, from about 65% to about 99.9% hydroxypropylcellulose, and from 0% to about 30% plasticizer, preferably water.

The following examples illustrate the invention.

Example 1

The following aqueous solutions were prepared:

Solution A

pilocarpine base 2.08 g alginic acid 2.42 g hydroxylpropyl Lise lululose (K.LUCEL GF) 0.45 g water 30 ml

Solution B

pilocarpine base 2.08 g alginic acid 2.42 g hydroxypropyl seululose (KLUCEL HF) 0.45 g water 30 ml

Solution C

pilocarpine base 2.08 g alginic acid 2.42 g hydroxypropylcellulose (KLUCEL OF) 0.45 g water 30 ml

Thin films were prepared by casting from these solutions and then cutting from the dry films rectangles of 6,58433 with dimensions of about 3 mm x 10 mm. The in vivo disappearance time of these ophthalmic inserts and the total opacifying effect were determined as follows:

Experimental animals were used in a group of six randomly selected male and female New Zealand albino rabbits weighing 3 to 3.5 kg and approximately 4-5 months of age. Animals were housed in closed boxes in a constantly dimly lit room. Young animals were performed under experimental conditions (laboratory, storage boxes ...) once before the time of testing. The same rabbits were reused with an interval of at least 14 days between two experiments; finally, they were no longer used for experiments after 5 times. The animals were acclimated to the environment for one hour and, after initial measurements, test compounds (solutions, rods, plates, ointment ...) were administered to the conjunctival sac of one eye and the other untreated eye served as a control. Eye blade measurements were performed at 5, 30, 90, 210, and 360 minutes after treatment. The mean eye-blade diameters and safety margins p ^ 0.05 for each series (6 rabbits) were recorded.

The diameter of the eyeball was measured with a pupillo meter from LUNEAU and COFFIGNON, the operating principle of which involves placing the actual image of a beam of red light of varying diameter at the level of the iris. The adjustable diaphragm adjusts the diameter of the red light beam so that it coincides with the diameter of the eyeball. The diameter of the diaphragm is recorded directly in millimeters. The results of these experiments are shown in the following table:

Preparation Disposal time mg pilocarpine Miotic total no. (Minutes) per insert activity JS insert / myotic total activity ___activity Vk solution__ A 10 <t <30 4.01 23 = 20.7

B 120 <t <240 4.56 26.3, cc KM

16.6

C 240 <t <300 5.77 34.1 2 QQ M

16.4

IS

Total miotic activity is equivalent to the total biological response and is expressed as the area under the curve 7 58433, which indicates changes in mesh size from the time of dose until the size of the mesh has returned to the reference diameter. The area of the reaction curve is obtained graphically from the representation where the ordinate is the size of the eye blade and the abscissa is the time and the comparison is made between the treated eye and the reference eye.

SOK

The effect is much better than with the solution after 210 minutes.

Example 2

A mixture of 25 g of 60 mesh pilocarpine pamoate and 75 g of 60 mesh hydroxypropylcellulose (K.LUCEL HF) is thoroughly mixed using conventional dry powder mixing methods such as mortar and pestle, twin jacket mixer, planetary mixer and the like. The mixture is then passed through a 30 mesh screen and mixed again. A small amount (2 to 5 g) of the mixture is then placed in the center of a clean, dry aluminum sheet 7 mm (0.2755 in.) Thick, the surface of which is coated with a lubricant such as aerosol lecithin and a thickness adjuster about 1 mm thick (spacer ) is placed in each of the four corners of the aluminum plate. A second lubricated 7 mm thick aluminum plate is placed above the first plate and the plates are transferred to a hydraulic press as named Model B Carver 2 2

Press into a known press between two 15.2 cm x 15.2 cm plates equipped with means for heating and cooling. The top and bottom surfaces of the plates are preheated to 93.3 ° C. The press is then closed and the material is brought to a gauge pressure of 700 kg / cm while maintaining the plates at the same temperature. After one minute, cold water is circulated inside the plates to cool the product while releasing the pressure and removing the product in the form of a thin plate. It is then cut into small rectangles measuring 10 mm x 4 mm and about 0.6 mm thick, containing about 2 to 4 mg of pilocarpine per unit dose.

The ophthalmic inserts thus obtained were tested for miotic activity in rabbits using the methods described in Example 1. At the same time, a standard pilocarpine solution treating an equivalent dose of pilocarpine was administered to one group of rabbits.

58433 The results of these experiments are shown in the following table:

The average diameter of the eye blade - e.g.

Time Comparison Ordinary pilocarpine- Rectangular pilo- (hours) solution of carpine pamoate ____________ inserts__ 0 7.5 1/2 7.3 5.2 5.2 1 1/2 7.3 5.6 4.8 3 1/2 7, 4 6.7 5.0 6 7.5 7.4 5.5 7 7.4 --- 5.7 Θ 7.4 --- 5.6 9 7.4 --- 6.3 10 7, 4 --- 6.8

The table above shows the prolonged miotic effect achieved when pilocarpine is administered in the form of a rectangular insert formed with hydroxylpropylcellulose.

The above-mentioned ophthalmic inserts are placed in a cabinet and exposed for two days to room temperature air with a relative humidity of ΘΘ%. The initial weight of the sieve inserts increases by about 10 mg to 20 mg in two days, which means the binding of 2 mg of water, i.e. about 11% of the total weight of the insert. The plasticizing effect of water makes the insert much softer and more flexible.

Example 3

A mixture of pilocarpine pamoate and hydroxypropylcellulose prepared as described in Example 1 is used to prepare an extruded fiber in a conventional extruder as follows.

The heating controller of the Custom Scientific Instrument Mini-Max Molder (Model CS-1Q3) is set to 200 ° C. After the device is sufficiently heated, the rotor operating switch is turned on and about 0.5 g of the loose powder mixture is fed into the cup. A filament of the desired diameter (less than 1 mm to 2 mm) is obtained by drawing the extruded filament under continuous drawing. In this case, the force exerted on the hot extruded product determines the diameter of the strand. The rod-shaped strands thus prepared are cut into pieces of about 10 mm in length with a picocarpine content of 1.9 mg. These are tested for the miotic response in the rabbit eye using the test method described in Example 1 and the results are shown in the following table:

Average eye blade - e.g.

Time Comparison Extruded thread [hours] _____ 0 7.5 1/2 7.4 5.3 1 1/2 7.3 5.3 3 1/2 7.4 5.9 6 7.4 5.5 7 7 , 5 5.7 8 7, 5 6.0 9 7.6 6.2

The ophthalmic inserts described above are placed in a cabinet and exposed to room temperature air at a relative humidity of 88% for 2 days. The initial weight of the ophthalmic inserts of about 18 mg increases to a weight of 20 mg within 2 days, indicating the binding of 2 mg of water, i.e. about 11% based on the total weight of the insert. The plasticizing effect of water makes the insert much softer and more flexible.

Ophthalmic inserts can also be injected into the mold using the same device and a 1- or multi-cavity mold.

Example 4

A mixture of 16.25 parts by weight of 60 mesh pilocarpine nitrate and 83.38 parts by weight of hydroxypropylcellulose is mixed thoroughly and 8.37 parts of propylene glycol are added to this mixture in a high shear mixing device. A small amount of the resulting mixture is then compressed using the methods described in Example 2 to form a thin solid sheet from the mixture, which sheet is cut into rectangular inserts having dimensions of about 10 mm x 4 mm and a thickness of about 0.8 mm. The ocular inserts thus obtained, containing 3.4 mg of pilo-carpine, were tested in the rabbit eye for a myotic response and the results were as follows: 10,58433

The average diameter of the eye blade - e.g.

Time Comparison Rectangular insert (hours) ________ 0 7.3 1/2 7.2 4.7 1 1/2 7.2 4.6 3 1/2 7.3 4.6 6 7.3 5.9 7 7 .3 5.9 8 7.3 6.2 9 7.3 6.4 10 7.3 6.9

Example 5

A mixture of 17.5 parts by weight of pilocarpine alginate a, 74.25 parts by weight of hydroxypropylcellulose (KLUCEL HF) and 8.25 parts by weight of propylene glycol is mixed according to the methods described in Example 4. The resulting mixture is compressed following the methods described in Example 2 to obtain a thin film which is cut to form rectangular inserts measuring 10 mm x 4 mm with a thickness of about 0.8 mm. These inserts containing about 2.2 mg of pilocarpine were tested in rabbit eyes by the test procedure described in Example 1 and the results are as follows.

Average diameter of the eyeball - e.g.

Time Comparison, Rectangular insert (hours) ____________________________________ 0 7.3 1/2 7.3 4.3 1 1/2 7.3 4.5 3 1/2 7.3 4.8 6 7.3 5.3 7 7.5 6.2 8 7.7 6.9 9 7.5 6.9

Example 6

The standard solution of pilocarpine and the method of Loucas et al. the miotic activity of the solid pilocarpine alginate insert prepared as described in Example 1 is compared using the rabbit test method described in Example 1. In these experiments, 58433 11 Pilocarpine doses of 9.7 mg are used. The miotic responses are shown in the following table:

The average diameter of the mesh - e.g.

Time ^ Comparison Equivalent dose of pilocarpine (hours) ______pilocarpine solution_a lgi naatt i_ 0 7.5 1/2 7.5 4.6 4.8

1 1/2 7.5 4.9 4, B

3 1/2 7.5 7.2 5.3 6 7.5 7.4 6.6 7 7.5 --- 7.2

Claims (4)

58433 A process for preparing an ophthalmic preparation, characterized in that a mixture of 0.1 to 35% of ophthalmically active drug, 65 to 99.9% of hydroxypropylcellulose and 0 to 30% of plasticizer is formed in a manner known per se, for example by molding or injection or extrusion. , as a film or rod having a thickness of preferably 0.5 to 1.5 mm, respectively. A method according to claim 1, characterized in that the solid ophthalmic preparation is formed from the cooled mixture into a dosage form. A method according to claim 1 or 2, characterized in that the solution of the mixture is evaporated to form a thin, solid body which is divided into pieces to form an ophthalmic preparation. Method according to one of Claims 1 to 3, characterized in that the ophthalmically active drug is a miotic agent or pilocarpine.