DD294174A5 - OPHTHALMIKA WITH RESET EFFECT AND A NEW PROCESS FOR THEIR MANUFACTURE - Google Patents

Abstract

The invention relates to a novel process for the preparation of ophthalmic preparations with a sustained action on the basis of a copolymer of acrylic and methacrylic acid (base gels) and active ingredients. The processing of active ingredient-containing base gels or specially prepared active compound gels allows the production of drippable formulations, primarily in the weakly acidic, euhydrischen p H range, for many ophthalmologically effective drugs, including those with the addition of isotonic and preservatives. {Pharmaceutical process; Ophthalmika; Acrylic acid copolymers; base gels; Wirkstoffgele; lyophilized polymer salts; drop-wise preparations with sustained-release action; Stabilitaetsoptimierung}

Description

Field of application of the invention

The present invention relates to a novel production process of novel ophthalmic preparation.

Characteristic of the known state of the art

Extended-effect ophthalmic drugs are an important requirement for many pharmaceuticals and indications. They are of particular value in glaucoma therapy. Various efforts to develop such patient-friendly and side-effect-free dosage forms for long-term medication led via oils and ointments to gels, inserts and therapeutic systems or to the use of alternative agents, such as β-receptor blocker, for example, the classic pilocarpine. However, these drug forms or drugs are not universally applicable and not without criticism remained (visual impairment, mechanical irritation, difficult handling, side effects, etc.). Therapy demands of the ophthalmologists therefore include the availability of eye drops with reduced application frequency, based primarily on the established pilocarpine.

The concern of the effect extension was often by using viscosity-increasing macromolecules, u. a. various cellulose derivatives, polyvinyl alcohol, polyvinylpyrrolidone, etc., mostly with unsatisfactory success, trying to solve. Likewise, polyacrylic acids, in particular Carbopol® (B.F-Goodrich, USA, molecular weight about 4 mill.), Have been tested and described as an excellently compatible ophthalmic vehicle (Bottari, F., and co-workers; Farmaco, Ediz., Pract. 33,434 [1978]). However, previous applications are limited to eye gels or eye liner tests. The preparation of clear, aqueous polyacrylic acid solutions of suitable concentration and pH has proven to be problematic. Most ophthalmic pharmaceuticals require efficacy, physiological compatibility, and chemical stability to have low hydrofluoric pH values in which insoluble polyacrylic acid precipitates. In addition, known viscous polyacrylic acid formulations are extremely sensitive to electrolyte additions and pH shifts. Thus, cations greatly reduce the consistency and may lead to coagulation (Redler, H.P.-Lexicon of excipients-Editio Canter Aulendorf, 1989, p.256.959).

In DE-OS 2636559 are from copolymers that u. a. Acrylic acid or methacrylic acid may contain as hydrophilic components in addition to various hydrophobic components, described salts with basic drugs. Eyepiece applications, e.g. the corresponding Pilocarpinsalze, as solid (eye deposits), optionally as an emulsion listed. Known disadvantages of the use of these films are difficulties in loading, slipping in the eye, uncontrolled drug delivery u.a. When the emulsions are used, obstructions and stability problems are observed.

Object of the invention

With the new manufacturing process, such new ophthalmological preparations should be obtained with known active ingredients which avoid the difficulties mentioned in terms of handling and the defined long-term active ingredient release and leave no visual obstruction in the patient.

Explanation of the essence of the invention

It is proposed to develop as low-ophthalmic preparations with retard effect as possible for primarily cationic, known active substances.

According to the invention, known per se, dissolved in Aqua sterilisata, pharmaceutical active ingredients with a base gel of a known copolymer of monomeric acrylic and methacrylic acid with a molar mass of 500,000 to 1,000,000 and a carboxyl group content of 30 to 40% after treatment with a per se known neutralizing agent in sterile aqueous suspension to a pH of 5.9-6.5 added. After complete swelling at room temperature is diluted with aqua sterlisata to a viscosity of 0.010-10Pa s.

According to the invention, a large number of different, known in the weakly acidic range, effective ophthalmic drugs depending on the pH range set according to the invention can be used, for example, alkaloids, local anesthetics, antibiotics u. a.

The copolymer (PAS-F) corresponds to the purity requirements for carbomer of USP XXI or for polyacrylic acid DAB 9 compatibility tests in animal and human experiments (DRATZE test: Draize, J. Woodard, G., Calvery, H .; J. Pharmacol , exp. Therapeut., 81, 3711, 944]) have PAS-F preparations both conjunctivally and corneal as irritant-tolerated. Suitable neutralizing agents are, for example, aqueous sodium hydroxide solution, triethanolamine or pilocarpine base / sodium hydroxide solution. Preferably, a process according to the invention consists in adding 30.0 g of hydrochloric acid (0.1 mol / l) slowly to 50.0 g of base gel with stirring. The resulting mixture is sterilized according to official pharmacopoeia regulations. Subsequently, 2.0 g of pilocarpine hydrochloride, optionally dissolved with the addition of a known preservative under aseptic conditions in 17.0g Aqua sterilisata. The solution thus obtained is filtered bacteria-free in accordance with the official pharmacopoeia regulations and incorporated slowly into the cooled hydrochloric acid-adjusted base preparation with continued stirring. As a preservative, for example, based on the above ratios, 0.01 g of benzalkonium chloride together with 0.1 Og sodium edetate or 0.002 g thiomersal suitable.

A preferred method for preparing a pilocarpine-based ophthalmic drug is to mix under aseptic conditions 7.0 g of copolymer with 76.3 g of Aqua sterilisata to a suspension containing 15.0 g of sodium hydroxide solution (3 mol / l) and 1.7 g of pilocarpine base are added with stirring, whereby a pH of 6.5-6.6 reached and after completion of the addition for about 5min further mixed well. The active ingredient gel remains covered for 48 h at room temperature until completely swollen and can be used immediately, optionally with further dilution. Another preferred method according to the invention for the preparation of a Pilocarpinpharmakons is characterized in that 1.4 g of copolymer with 2.0 to 4.0 g pilocarpine base are suspended in a glass mortar in aqua and 24 h remain at room temperature. The resulting clear gels are then lyophilized. If necessary, the amount equivalent to the required amount of drug, optionally with the addition of an isotonizing agent, dissolved in Aqua sterilisata. As the isotonizing agent, for example, sodium chloride or mannitol are suitable. The advantages according to the invention can be summarized as follows:

- PAS-F preparations are colorless and clear and prove to be physically and chemically stable during sterilization and storage. Non-electrolytes (mannitol, sorbitol) are preferably suitable for isotonization, whereas electrolytes (sodium chloride) increase the release of active substance due to a displacement of active substance cations from the Pölymer bond.

Salting of active substance bases (for example pilocarpine) with PAS-F in an aqueous medium and subsequent lyophilization can be used to prepare polymer salts which, depending on the amount of polymer used, lead to considerably delayed release of the active ingredient in comparison to the excipient-free drug solution.

- Miosis testing in rabbits of preparations containing PAS-F (1-7% or polymer salts) gave relative bioavailabilities of 122-170% compared to the polymer-free drug solution (pilocarpine). Here, preparations are of gel consistency (viscosity 1,3-8,8Pa · s; D = 16,2s ~ \ RHEOTEST; 37 ° C) the droppable preparations (viscosities 25OmPa · s; Kugelfallviskosimeter; 37 ⁰ C) with respect to their active extension not superior , however, have therapeutically favorable plastic phases in the miosis-time curve.

In the orienting human experiment, both myostasis tests and the recording of intraocular pressure (IOP) showed a significant prolongation of activity and, in contrast to the results of the animal experiments, also active enhancement of the active ingredient-containing PAS-F and the polymer salt preparations compared to the standard preparation (aqueous pilocarpine solution of the same type Concentration). While the lOP is reached again after application of polymer-free pilocarpine solutions after about 6 h, polymer-containing test preparations of the PAS-F (7%) and of the polymer salt (1: 1.6) are still effective after 8.25 h.

Compared to the relative bioavailability (up to 6.5 h) of the active ingredient from polyacrylate-containing preparations of about 200%, calculated using the lO-time curves, the bioavailability calculated using the miosis-time curves is about 130%. This is to be considered therapeutically advantageous, since the Miosis occurs as unwanted side effect of the Pilocarpins.

With regard to the reduction in lOP below 2.8 kPa (21 mm Hg), which was the goal in glaucoma therapy, the aqueous, polymer-free active substance solution proved unfavorable both in its duration of action and in its potency; it merely resulted in a one hour maximum pressure drop to 2.8 kPa (21 mm Hg). In contrast, with the tested Polyarylatzubereitungen a ca. 4V2Stündige therapeutic pressure reduction with a maximum efficacy of 2.4kPa (18 mm Hg) achieved.

Although the bioavailability of the active ingredient from PAS-F preparations is increased compared to the standard polymer-free preparation, the side effects produced by pilocarpine are not more pronounced.

As for the subjective compatibility, the polymer salt preparation is preferred. Higher concentration PAS-F preparations produced mild adhesions and foreign body sensations.

- After human trials, PAS-FzurFormulierungophthalmoIogischer drug preparations with protracted action proved to be suitable. Due to their high bioavailability, which is comparable to hydrogel preparations and has been enhanced by potentiation and prolongation, the most favorable variants are dripable preparations of pilocarpine salt. The polymer salt, as a lyophilizate, also offers advantages in terms of active ingredient stability during storage.

The drippability of the PAS-F preparations and the drug stability could be further optimized according to Examples 7 and 8 by pH regulation with hydrochloric acid (at the same time isotonization). In vitro release levels <50% were achieved compared to the polymer-free standard solution. Oriented human trials showed definite extension of action (IOP measurement).

embodiments I. Basic preparations

It was used as polyacrylic acid, a product of Fa. Fluka, Switzerland, (PAS-F).

Example 1 PAS-F7% / Na (100% tg neutralized)

Polyacrylic acid PAS-P 7.0 g pH: 6.4-6.5

NaOH (3mol / l) 18.0g Viscosity: 6.90-6.91 Pa-S (D = 16.2S " ¹ , Rheotest, 37 ° C)

Aqua to 100.0 g

Example 2 PAS-F7% / TEA (100% Neutralized)

Polyacrylic acid PAS-F 7.0 g pH: 6.4-6.5

Triethanolamine 7.0 g Viscosity: 8.77-8.78 Pa · s (D = 16.2 s ^-1 , Rheotest 37 ° C)

Aqua to 100.0 g

Example 3

Polyacrylic acid PAS-F 7.0 g pH: 5.95-6.15

NaOH (3 mol / l) 10.0 g Viscosity: 1.60-1.65 Pa - s (D = 16.2 s ^-1 , Rheotest, 37 ⁰ C)

Aqua to 100.0 g

Preparation of the preparations: PAS-F is suspended in the total amount of water, the neutralizing agent (NaOH or triethanolamine or pilocarpine base / NaOH [see Example 4]) is added with stirring and the mixture is stirred for about 5 minutes. gutdurchmischt. The base gels remain covered for complete swelling for 48 h at room temperature and are then sterilized by the method aides AB-DDR.

From these examples, appropriate dilutions are made with Aqua. Active ingredients, isotonizing agents and preservatives are to be dissolved in Aqua sterilisata, filtered sterile and aseptically to incoporate into the base gels (see Examples 7-10).

H. Active substance-containing preparations

Example 4 PAS-F7% / PS (100% Neutralized)

Polyacrylic acid PAS-P 7.0 g pH: 6.5-6.6

Pilocarpine base 1.7 g Viscosity: 8.76-8.77 Pa · s · (D = 16.2 s ^-1 , Rheotest, 37 ⁰ C)

NaOH (3moI / l) 15.0 g

Aqua sterilisata to 100.0 g

Production s. O. Example 5 Pilocarpine hydrochloride 2.0 g pH: 6.4-6.5

NaCl 0.3 g Viscosity: 35-38 mPa-s Osmolarity: 289-292 mOsm / kg

PAS-F1% to 100.0 g

(diluted, from Ex. 1)

Example 6 Pilocarpine hydrochloride 2.0 g pH: 6.6-6.7

PAS-F3.5% viscosity: 1.33 Pa - s (D = 16.2 s ^-1 , Rheotest, 37 "C)

(diluted from Ex. 1) to 100.0 g

Example 7

Base preparation Ex.3 50,000 g pH: 5.4-6.5

Pilocarpine hydrochloride 2,000 g Viscosity: 18-22 mPa.s Osmolarity: 265-272 mOsm / kg

Thimerosal 0.002g

Hydrochloric acid (0.1 mol / l) 30,000 g

Aqua to 100,000g

Example 8

Base preparation Ex. 3 50.00 g pH: 5.4-5.5

Pilocarpine hydrochloride 2.00 g Viscosity: 16-21 mPa · s Osmolarity: 295-310 mOsm / kg

Benzalkotassium chloride 0.01 g

Sodium edetate 0.10 g

Hydrochloric acid (0.1 mol / l) 30.00 g

Aqua to 100,00 kg

Preparation Examples 7 and 8: The hydrochloric acid is slowly added to the base preparation with stirring (complete homogenization) and then sterilized by the process ai of AB-DDR. Under aseptic conditions pilocarpine hydrochloride and the corresponding preservatives are dissolved in the remaining amount of aqua, filtered baktierenfrei according to method d of AB-DDR and slowly incorporated with constant stirring in the cooled hydrochloric acid-adjusted base preparation.

Example 9

Base Preparation Ex. 3 50,000 g pH: 5.9-6.0

Thiomersal 0.002 g Viscosity: 66-73 mPa · s Osmolarity: 295-305 mOsm / kg

Mannitol 2.200 g

Carbachol 1,000 g

Aqua to 100,000 g

Example 10

Base Preparation Ex. 3 50,000 g pH: 6.9-7.0

Chloramphenicol 0.500 g Viscosity: 490-520 mPa · s Osmolarity: 295-320 mOsm / kg

Thimerosal 0.002 g

Boric acid 1.200 g

Sodium tetraborate 0.300 g

Aqua to 100,000 g

Preparation of Examples 9 and 10: The respective drug and the further adjuvants are added to In auras sterilisata, u.U. under heating, dissolved. The solution is filtered bacteria-free and incorporated under aseptic conditions with constant stirring in the sterilized base preparation.

III. Polymer salts (PPS)

Example 11 PPS 1: 1.6

Polyacrylic acid PAS-F 1.40 g

Pilocarpine base 2.24 g

Aqua to 10.00 g

Example 12 PPS 1: 2.5

Polyacrylic acid PAS-F 1.40 g

Pilocarpin base 3.50 g

Aqua to 10.00 g

Preparation of Examples 11 and 12: PAS-F and pilocarpine base are suspended in the corresponding ratio in Aqua and allowed to stand at room temperature for 24 h. The resulting clarified gels are then lyophilized. The products shredded in the mortar are stored in a desiccator over silica gel.

To prepare the polymer salt solutions, equivalent amounts of PPS in aqua sterilisata are dissolved in the required amount of drug; in the case of isotonization, simultaneously with isotonizing agent (Examples 13 and 14).

Example 13

PPS1: 1.6 (Ex.11) 2.76gpH: 6.4-6.5

NaCl 0.80 g Viscosity: 30-33 mPa.s Osmolarity: 317-322 mOsm / kg

Aqua sterilisata to 100.00 g

Example 14

PPS 1: 1.6 (Ex. Π) 2.76 g pH: 6.9-7.0

Mannitol 5.00 g Viscosity: 235-235 mPa · s Osmolarity: 292-296 mOsm / kg

Aqua sterilisata to 100.00 g

Claims (4)

1. A process for the preparation of ophthalmic drugs with sustained release, characterized in that known per se, dissolved in Aqua sterilisata, pharmaceutical active ingredients with a base gel consisting of a known copolymer of monomeric acrylic and methacrylic acid having a molar mass of 500,000 to 1,000,000 and a carboxyl group content of 30 to 40% after treatment with a per se known neutralizing agent in sterile aqueous suspension is added to a pH of 5.9-6.5 and remains until complete swelling at room temperature, with Aqua sterilisata up to a viscosity of 0.010-10Pa s is diluted. 2. A process for the preparation of sustained-release ophthalmic drugs according to claim 1, characterized in that 30.0 g of hydrochloric acid (0.1 mol / l) are slowly added to 50.0 g base gel while stirring, the product is sterilized according to the official pharmacopoeia regulations , then with 2.0 g pifocarpine hydrochloride, which was dissolved under aseptic conditions in 17.0 g Aqua sterilisata, filtered bacteria-free according to the official pharmacopoeia regulations and slowly incorporated with slow stirring in the cooled hydrochloric acid-adjusted base preparation. 3. A process for the preparation of an ophthalmic drug with sustained release according to claim!, Characterized in that 7.0 g of copolymer are mixed under aseptic conditions in an aqueous suspension, the 15.0 g of sodium hydroxide solution (3 mol / l) and 1.7 g Pilocarpinbase are added with stirring until a pH of 6.5-6.6 is reached, after completion of the addition is further thoroughly mixed for about 5min and the product is allowed to stand for 48 h covered until complete swelling at room temperature. The active ingredient gel can be used immediately, optionally with further dilution. 4. A process for the preparation of a retarded ophthalmic drug according to claim 1, characterized in that 1.4 g of copolymerizate with 2.0 to 4.0 g of pilocarpine base are suspended in water, left at room temperature for 24 h and the resulting clear gels are subsequently lyophilized. If necessary, the amount of Lyophilisates equivalent to the required Azrneistoffmenge, optionally with the addition of an isotonizing agent, dissolved in Aqua sterilisata.