CS203980B2 - Method of production of solid ophtalmological inserts - Google Patents

Description

The invention relates to a process for the production of solid ophthalmic inserts for human and veterinary medicine, i.e. solid unit dosage forms containing therapeutically active substances and an inert matrix. According to the invention, hydroxypropylcellulose is used as the inert matrix.

In the usual treatment of various ophthalmic diseases, doses of suitable drugs are administered in aqueous suspensions, solutions or ointments. This treatment is satisfactory for the treatment of ophthalmic diseases where the drug has to be administered one or more times. However, some eye diseases require more frequent dosing, and such treatment is uncomfortable for the patient. It has recently been proposed to apply ophthalmologically active drugs in solid form to an inert matrix (see, for example, U.S. Patent No. 3,710,795). This method has the disadvantage that the inert matrix must be removed from the matrix after the drug has been completely released. Loucas et al. [F, of Pharm. Sci. St. 61, p. 985 (June 1972)] recently found that when a salt of alginic acid and pilocarpine is applied to a rabbit's eye as a solid ophthalmic insert, a greater miotic response is achieved than would be achieved with a conventional pilocarpine solution.

SUMMARY OF THE INVENTION It is an object of the present invention to provide improved ophthalmic inserts with a prolonged action which would allow to minimize the frequency of dosages required for the treatment of various eye diseases. It is also an object of the present invention to provide a medicament-containing ophthalmic insert that provides slow but continuous release of the drug into the lacrimal fluid while minimizing drug loss in the naso-lacrimal ways. It is also an object of the present invention to provide an ophthalmic insert which, when applied to the conjunctival sac of the eye, dissolves completely in the lacrimal fluid and therefore no drug-free substance needs to be removed. Other objects of the invention are apparent from the following detailed description.

According to the invention, the aforementioned requirements meet the ophthalmic inserts consisting of hydroxypropylcellulose and an ophthalmic drug. Suitable inserts, which can be prepared by the various methods described below, are prolonged-effect ophthalmic preparations when applied. The release of the drug from the ophthalmic insert is accompanied by gelation and finally dissolution of the matrix in the lacrimal fluid, thereby eliminating the need to remove the matrix from which the drug has been depleted before administering the next dose.

The present invention provides a process for the manufacture of solid ophthalmic inserts by mixing the active drug with an inert polymer matrix,

203960, optionally in the presence of a plasticizer, shaping the resulting melt mixture and optionally mechanically treating the resulting product, characterized in that hydroxypropylcellulose is used as the inert polymer matrix.

Hydroxypropylcellulose is a non-ionic, water-soluble cellulose ether which has properties particularly suited for the preparation of ophthalmic inserts. It is water-soluble and thus dissolves in an aqueous lacrimal fluid. In addition, hydroxypropylcellulose is thermoplastic and can therefore be combined with an ophthalmologic drug prior to unit dose administration using conventional plastics processing techniques such as compression, injection and extrusion. It is available in a variety of polymeric forms, all of which are suitable for preparing the ophthalmic inserts of the invention. For the preparation of the novel liners according to the invention, for example, conventional products which are intended for food and pharmaceutical use are suitable.

The compositions of the invention may be prepared in various ways. Thus, the drug and hydroxypropylcellulose can be dissolved in a suitable solvent, and then the solution is evaporated to form a thin film containing hydroxypropylcellulose and the drug, which can then be further subdivided to prepare suitable inserts containing the desired amount of drug. An alternative and preferred method of the invention is based on the ability to prepare the inserts while utilizing the thermoplastic properties of hydroxypropylcellulose. For example, the drug and hydroxypropylcellulose may be heated to 66-204 ° C together and the resulting mixture formed into a thin film. Typically, the inserts are preferably made by compression or extrusion methods well known in the art. The compressed or extruded product may then be further subdivided to provide inserts of a suitable size for ocular application. For example, films obtained by casting or molding of about 0.5 to 1.5 mm thickness can be further subdivided into suitable inserts in the form of squares, rectangles, circles, semicircles and the like containing the required amount of active ingredient. The rectangular segments of the cast or pressed film having a thickness of 0.5 to 1.5 mm can be cut into 4 X 5 to 15 mm rectangular plates or ovals of comparable size. Similarly, extruded bars having a diameter of about 0.5 to 1.5 mm can be cut into suitable sections to achieve the desired dose of drug. For example, rods with a diameter of 1.0 to 1.5 mm and a length of 10 mm are useful. The inserts may also be directly injection molded. All ophthalmic inserts prepared according to the invention must be shaped so that they do not have sharp edges or corners that could cause eye damage.

The liners manufactured according to the invention may also contain emollients to be more flexible. Of course, the emollients suitable for this purpose must also be completely soluble in the ophthalmic lacrimal fluid. Examples of suitable plasticizers include water, polyethylene glycol, propylene glycol, glycerin, trimethylolpropane, di- and tripropylene glycol, hydroxypropylsaccharose, and the like. Typically, these emollients may be present in the eye pad in an amount of from about 10 to about 30% by weight. %. A particularly suitable emollient is water, which is present in an amount of at least 5%, preferably at least about 10%. In practice, a water content of about 10 to about 20% is preferred, since such water content is readily achieved and this amount of water imparts the desired softness and pliability to the liner.

To soften a solid medical product with water, the solid medical product is contacted with air having a relative humidity of at least about 40% until the product has taken up at least about 5% of water and softens and becomes more pliable. In a preferred embodiment, air with a relative humidity of about 60 to about 99% is used and the inserts are in contact with the air until the water is present in the product in an amount of about 10 to about 20%.

Suitable drugs that can be administered with the inserts of the invention are, for example, antibacterial agents such as β-lactam antibiotics, tetracyclines, chloramphenicol, neomycin, gramicidin, bacitracin, sulfonamides, gentamycin, kanomycin, nitrofurazones and the like, antihistamines and decongestants such as pyrilane chlorpheniramine, tetrahydrazoline, antazoline and the like; anti-inflammatory agents such as cortisone, hydrocortisone, betamethasone, dexamethasone, fluocortolone, prednisolone, triamcinolone, indomethacin and the like; homatropin, scopolamine, hydroxyamphetamine, and the like, and other drugs used in the treatment of ocular diseases.

These medicaments or derivatives thereof, such as salts, derivatives with covalently bonded groups, for example esters or amides, or other therapeutically active forms, can be mixed with hydroxypropylcellulose for the treatment of various eye diseases and formulated as the water-soluble inserts described above. These forms are particularly useful for the treatment of diseases where prolonged administration of the drug is intended, for example in ocular diseases or conditions such as uveitis, glaucoma, corneal diseases such as purulent keratitis, herpes simplex keratitis, herpes zoster, acne rosacea, interstitial keratitis , and the like, orbital diseases such as exophthalmus and periostitis, and conjunctival diseases such as mucopurulent conjunctivitis and ophthalmia. This method of administering ophthalmologically active drugs may also be used when post-operative treatment is required following retinal surgery or ophthalmic lens opacifying.

This method of administering drugs in the form of water-soluble pads is particularly useful for the administration of pilocarpine in the treatment of glaucoma, a disease characterized by an increase in intraocular pressure. When administered with the ophthalmic inserts of the invention, a rabbit can achieve a miotic response of 9 to 10 hours compared to a shorter response of 2 to 4 hours achieved with drops. Pilocarpine may preferably be administered in the form of salts with acids such as hydrochloric, alginic, pamoic and the like. The ophthalmic insert of the invention may contain up to about 35 wt. % pilocarpine to achieve a dose of about 1 to 8 mg pilocarpine per pad.

Typically, the ophthalmic inserts of the invention comprise about 0.1 to about 35% of the drug, about 65 to about 99.9% of hydroxypropylcellulose and about 0 to about 30% of a plasticizer, preferably water. In special cases, however, the amounts may be varied to increase or decrease the dosage.

Sterilization of the inserts may be accomplished by any of a number of known methods. These methods are described in the International Atomic Energy Commission: Code of Practice for Radiosterilization of Medical Products, 1967, pages 423 to 431 and Block: Disinfection, Sterilization and Preservation, 2nd Ed. Lea and Febiger, Philadelphia 1977, pages 542 to 561. .

The following examples describe specific processes for preparing the novel ophthalmic inserts of the invention and serve to illustrate specific features of the invention.

Example 1

The following aqueous solutions are prepared:

Solution A pilocarpine (base) 2.08 g alginic acid 2.42 g hydroxypropylcellulose (KLUCEL GF) 0.45 g water 30 ml

Solution B pilocarpine (base) 2.08 g alginic acid 2.42 g hydroxypropylcellulose (KLUCEL HF) 0.45 g water 30 mi

Solution C pilocarpine (base) 2.08 g alginic acid 2.42 g hydroxypropylcellulose (KLUCEL JF) 0.45 g water 30 ml

Films are made from these solutions by casting and the dried films are cut into rectangles approximately 3 x 10 mm in size. For ophthalmic inserts obtained, the "disappearance time" and the total in vivo miotic effect are determined as follows:

Randomized groups of six male and six female New Zealand albino rabbits weighing 3 to 3.5 kg and approximately 4 to 5 months of age are used. Animals are housed in cages in an area with uniform illumination of low intensity. The new animals are allowed to adapt to the experimental conditions (laboratory, cages, etc.) already before the time of testing. The same rabbits are reused, leaving at least 14 days rest between two trials. A total of five tests are excluded from the tests. The animals are allowed to habituate for 1 hour and after initial measurements, the compounds of interest (in the form of solutions, sticks, discs, ointments, etc.) are administered to the conjunctival sac of one eye, the other untreated eye being used for control. The pupil measurements are taken 5, 30, 90, 210 and 360 minutes after treatment. In each series (6 rabbits) the mean pupil diameter and confidence range for P ≥ 0.05 are determined. The pupil diameter is measured using a Luneau and Coffignon pupillometer, which works by creating an apparent image of a beam of red light of varying diameter over the iris area. Using the adjustable aperture, the diameter of the red light beam is adjusted so that the image overlaps with the pupil. The diaphragm diameter is given directly in millimeters. The results of these tests are shown in the following table.

Preparation

Time to disappear (minutes)

The amount of pilocarpine (mg) in the pad

Overall miotic effect *. pads / / total miotic effect * of the solution

AND 10 <t < 30 4.01 23 = 1.11 20.7 (B) 120 <t < 240 4,56 26.3 16.8 = 1.56 ** C 240 <t < 300 5.77 34.1 16.4 = 2.08 **

* The term 'total miotic effect' is equivalent to 'total biological response' and is expressed as the area under the pupil size change curve from the time of dosing until the pupil size returns to the control pupil projection value. The area under the biological response curve is subtracted from the diagram plotting the pupil size versus time in the treated and untreated eye.

** The effect is significantly better than the solution after 210 minutes.

Example 2

A mixture of 25 g of 60-mesh pilocarpine pamoate and 75 g of hydroxypropylcellulose (KLUCEL HFj of 60-mesh) is mixed thoroughly using conventional dry powder mixing techniques such as a mortar, a two-blade mixer, a planetary mixer, and the like. The mixture is then passed through a 30 mesh screen and blended again, and a small amount (2 to 5 g) of the mixture is then placed in the center of a clean, 7 mm thick, dry-coated aluminum plate coated with a lecithin-coated aerosol. The first plate is then placed with a second 7 mm aluminum plate coated in the same way and the resulting formation is placed in a hydraulic press between two 152 x 152 mm pressure plates that can be heated The upper and lower pressure plates are pre-heated to 93.3 ° C. and the force is adjusted to 44.48 kN while the platens are maintained at the same temperature After 1 minute cold water is introduced into the platens to cool the product while maintaining the pressure at the original value. After about 2 minutes, the pressure is released and the wafer-thin sheet product is removed. The product is cut into small rectangles of about 10 X 4 mm, the thickness of which is about 0.8 mm. The unit dose of pilocarpine is about 2 to 4 mg.

The ophthalmic inserts thus obtained are tested for miotic effect in rabbits using the procedures described in Example 1. At the same time, one group of rabbits is administered an equivalent dose of pilocarpine as a conventional solution. The results of these tests are shown in the following table.

Pupil diameter (mm)

Time (hours) Checklist Common pilocarpine solution Rectangular inserts with pilocarpine pamoate 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 8 7.4 - 5.6 9 7.4 - 6.3 10 7.4 - 6.8

The above table shows that when pilocarpine is administered in the form of a rectangular pad formed with the use of hydroxypropylcellulose, a prolonged miotic effect is achieved.

The ophthalmic inserts made as described above are placed in a chamber in which they are kept at room temperature in contact with air and relative humidity for 2 days. 89 ° / o. The initial weight of the inserts, which is about 18 mg, will increase to 20 g in two days, indicating a retention of 2 mg, i.e. about 11% water, based on the total weight of the insert. The softening effect of the water results in the liner being much softer and more supple.

Example 3

Mixtures of pilocarpine pamoate and hydroxypropylcellulose prepared as described in Example 2 are used to prepare extruded fibers. Extrusion is carried out in a conventional extruder as follows:

The temperature control on the device (Custom Scientific Instrument Mini-Max Molder, Model CS-183) is set to 200 ° C. When the device is sufficiently heated, the rotor drive switch is turned on and about 0.5 g of coarse powder mixture is metered into the cup. A fiber of the desired diameter (less than 1 mm to 2 mm) is obtained by drawing the extrudate while continuously withdrawing. The force exerted on the hot extrudate determines the fiber diameter. The staple fiber thus produced is cut to a length of about 10 mm. The inserts obtained, containing 1.9 mg pilocarpine, were tested for miotic response in the rabbit eye using the procedure described in Example 1. The results are shown in the following table.

ÍO

Pupil diameter (mm)

Time (h) Control Extruded fiber

7.5

1/2 7.4 5.3

1/2 7.3 5.3

1/2 7.4 5.9

7.4 5.5

7,5 5,7

7,5 6,0

7.6 6.2

The ophthalmic inserts produced as described above are placed in a chamber in which they are kept at room temperature for 2 days in contact with air having a relative humidity of 88%. The initial weight of the inserts, which is about 18 mg, will increase to 20 g in two days, indicating a retention of 2 mg, i.e. about 11% of water, based on the total weight of the insert. The softening effect of the water results in the liner being much softer and more supple.

Ophthalmic inserts can also be made by injection molding with one or more cavities using the same device

Example 4

Mixture of 16.25 parts by weight. pilocarpine nitrate having a grain size of 60 mesh and 83.38 wt. The mixture is thoroughly mixed and 8.37 parts of propylene glycol are added to the mixture in a high shear mixer. A small amount of the resulting mixture is then compressed using the procedure described in Example 2 into a thin solid sheet, which is then cut into rectangular inserts of about 10 x 4 mm and about 0.8 mm thickness. The ophthalmic pads containing 3.4 mg pilocarpine thus obtained are tested in the rabbit eye for miotic response. The following results are obtained:

Pupil diameter (mm)

Time (h)

Checklist

Rectangular insert

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

Mixture containing 17.5 wt. % of pilocarpine alginate, 74.25 wt. % of hydroxypropylcellulose (KLUCEL HF) and 8.25 wt. A portion of propylene glycol is blended as described in Example 4. The resulting mixture is compressed as described in Example 2 into a thin film which is cut into rectangular inserts of 10 x 4 mm and a thickness of about 0.8 mm. Inserts containing about 2.2 mg pilocarpine are tested in the rabbit eye according to the test procedure described in Example 1. The following results are obtained:

Time (h)

Pupil diameter (mm)

Control Rectangular Insert

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 of the pu described by Loucas et al. (See above) using the rabbit test procedure,

The miotic effect of the standard described in Example 1 is compared. In these tests, a pilocarpine solution and a solid insert from an al dose of 9.7 mg pilocarpine are used. Pilocarpine mioticginate prepared according to the postural response is shown in the following table.

Pupil diameter (mm)

Time (h) Control

Equivalent Dose Pilocarpine Alginate Solution Pilocarpine

0 7.5 1/2 7.5 1 1/2 7.5 3 1/2 7.5 6 7.5 7 7.5

4.6 4.8 4.9 4.8 7.2 5.3 7.4 6.6 - 7.2

Example 7

To prepare pilocarpine pamoate, 20.7 grams of pilocarpine is dissolved in 20 ml of water and a stoichiometric amount, i.e., 19.3 g, of pamoic acid is added to the solution. The mixture was stirred for 3 hours until a homogeneous brown oil formed. The mixture is placed in a desiccator, which is maintained at 50-60 ° C under a vacuum of 74.660 kPa. Each day, the oil container is removed from the desiccator and the portion of oil that has dried on the surface is separated and ground to a powder. The vial with the remaining oily-yellow mixture is then placed in a heated vacuum desiccator. This process is repeated until all the oil has dried and is removed from the container. The yield is over 90 percent. The product contains 3.15% moisture. Analysis:

calculated: N 6.98%, C 67.31%, H 5.77%;

Found: N 6.8%, C 64.75 O / o, H 6.17%.

N 7.14%, C 65.01%, H 6.15%.

calculated with correction for water content:

N 6.76%, C 65.19%, H 5.95%.

Claims (1)

A process for the preparation of solid ophthalmic inserts by mixing the active drug with an inert polymer matrix, optionally in the presence of a plasticizer, shaping the resulting mixture of ynAlez melt and optionally mechanically treating the resulting product, characterized in that hydroxypropylcellulose is used as the inert polymer matrix.