DE4225489A1 - Aq. eye-drops contg. adhesive bio-polymer, e.g. polyvinyl alcohol and acid - adhere well to the cornea, provide better and longer lasting delivery of active ingredient e.g. pilocarpine - Google Patents

Abstract

Prodn. of bio-adhesive eye drops comprises adding to the usual vehicle (water for injection) (a) a water-swellable, bio-adhesive polymer (I) contg. hydrophilic (esp. OH and/or COOH) functional gps.; (b) an acid and (c) if needed an isotonicity agent. USE/ADVANTAGE - The drops are used to deliver e.g. pilocarpine or beta-blockers to the eye, e.g. for treating glaucoma. The compsn. can be applied as drops; is non-imitating and adheres well to cornea so that active ingredients penetrate well (even into deeper structures in the eye), providing better and/or longer lasting bio-availability. The compsn. spreads well (covering a large area of tissue for resorption) and the active ingredient is stable and protected against microbial degradation.

Description

Field of application of the invention

The invention relates to a process for producing a drippable, non-irritating, bio ophthalmic adhesive, which in addition to the active ingredients is a bioad containing a sticky excipient, an acid and optionally other excipients. The doctor After application, the agent sticks to the cornea of the eye for a long time, so that the active ingredients contained stronger than normal eyes Medicines in the cornea and / or in deeper parts of the eye get better and longer for a local or systemic effect become biologically available.

Characteristic of the known state of the art

For about 15 years, bioadhesive medicines are known that are sometimes given to biolo adhere to the tissue and thereby release the active ingredients. Of these Bio- or mucosa-adhesive medicines are expected due to the mucous membrane a solution to bioavailability problems resulting from too short a because of the time the active ingredients grow at the absorption site. In particular, bioad häsive drugs on certain mucous membranes, z. B. also on the cornea of the Auges, the drug preferably bring to absorption.

The adhesion of these drug forms at the site of absorption by bioadhesive polymers of which hydrogel formers, such as cellulose derivatives (hydroxyethyl cellulose (HEC), sodium carboxymethylcellulose (NaCMC)), polyacrylic acid (Carbopol®) and other carboxyvinyl polymers (Eudragit®), tragacanth and alginates have the strongest effect should have. In a review (Duchene, D .; Touchard, F., Peppas, N.A .: Drug Dev. Ind. Pharm. 14, 283 (1988)), bioadhesive drugs, e.g. Tablets, films, Patches, gels and capsules which have local or systemic effects wrinkles and those mainly orally (buccal), but also peroral (gastrointestinal tract), periocular, nasal, vaginal or rectal. On an application on the cornea of the eye was not discussed in this connection. When bioadhesive polymers were at this point carboxyvinyl polymers (Carbopol®, Polycarbophil®) and cellulose derivatives (hydroxypropylcellulose (HPC), HEC, NaCMC) or mixtures of both components. In particular, are suitable Carboxyvinyl polymers and compounds derived therefrom as bioadhesive  Polymers (Peppas, N.A .; Buri, P.A., J. Controlled Release 2, 257 (1985); Park, K .; Cooper, S.L .; Robinson, J.R .: Hydrogels Med. Pharm. 3, 151 (1987)). For example describe Bremecker and Mitarb. (Arzneim. Forsch. 33, 591 (1983), DE 34 00 106) a mucosa-adhesive polyacrylate-based gel that works well on the oral mucosa adheres and causes no skin irritation. Also for this gel becomes an oculare An not described.

Furthermore, a bioadhesive, water swellable but insoluble in Carb is oxylfunktion supporting polymer in USP 46 15 697 as an excipient for bioadhesive Arz mentioned. In this case, 80-95% of the monomers contain at least one Carboxylfunktion, which is a structural component of the copolymerized acrylic acid. The Successor patent USP 4,795,436 includes methacrylic acid as an additional possible bio Adhesive monomer. Evidence of an ocular application of this bioadhesive We did not find any medicines.

DD 282 551 A5 relates to a process for the production of bioadhesive medicaments, for example, tablets, granules, slimes containing a water-swellable Co polymer with at most 25% by weight of monomers with carboxyl contain functions that essentially by a foreign matter content of maxi times 0.56 parts by mass in% and further characterized by the fact that it under Ver use of a maximum of 0.5% by weight in% of an anionic emulsifier and of a maximum of 0.06 parts by mass in% of an initiator is produced. Also in this There are no indications of an ocular application of the copolymer.

In the sense of an ocular application are still only viscous solutions and Particulate drugs with bioadhesive effect described. These include For example, solutions, gels and matrices as well as an ophthalmic depot preparation based on nanoparticles and an eye pill.

The previously described solutions, gels and matrices are esp especially drug forms with hyaluronic acid, polyacrylic acid (Saettone, M. F .; Chetoni, P .; Torracca, M.T .; Burgalassi, S .; Giannaccini, B .: Int. J. Pharm. 51, 203 (1989)), Carbopol® 934 (Davies, N.M., Farr, S.J., Hadgraft, J .; Kellaway, I.W .: Pharm. Res. S, 1039 (1991)) and Polycarbophil® (Middleton, D.L., Robinson, J.R .:

S.T.P. Pharma 1, 200 (1991)). These excipients allow the drug (in the aforementioned cases: pilocarpine, tropicamide and fluorometholone) Viscosity enhancement and bioadhesion prolonged residence time on the cornea of the eye. However, there is no evidence that the active ingredients stabilized and their passage through the cornea is specifically promoted. Furthermore, will an adhesive preparation (Benedict, C.V., Picciano, P.T .: US 5015677 of 1991) described that was processed with derivatives of Polyphenoleiweißen and in the Orthopedics, on the eye and in dentistry can be used.  

The ophthalmological depot preparation (Kreuter, J., Speiser, P., DE 37 22 837, 19. Jan. 1989) based on polymeric nanoparticles of cyanoacrylates. The eye tablet (Conte, U., La Manna, A., Colombo, P., Saettone, M. F., Gazzaniga, A., EP 316 838 from 14. Nov. 1988) consists of a matrix, a polymer jacket and optionally from a bioadhesive layer which indicates adhesion of the dosage form the cornea of the eye or on the mucous membrane of the conjunctival sac responsible for.

In the two aforementioned cases are particulate dosage forms, which in Presence in the conjunctival sac or on the cornea of the eye from the patient as be uncomfortable. This is certainly more the case with the tablet the case than with the nanoparticles. These become, according to the definition Fineness provided, probably not physically irritating. However, that is not to be exhausted by the polymerization technique used for their production conclude that monomers are contained in the particles, their eye irritation is well known.

The tablet has the additional disadvantage that only a limited area for the Re sorption of the drug is available. In this respect, it is not an unattractive, nonparticulate bioadhesive eye medicine known.

Object of the invention

The aim of the invention is to overcome the disadvantages of the previously known production methods for bioadhesive eye medicines, especially those in which the dosage form is particulate is to eliminate and to create a nonparticulate bioadhesive eye medicine, which exerts no irritating effect or secretes substances which have an irritant effect. The new eye medicine should be drippable and the eye as possible a large Cover tissue section, whereby the active ingredients contained a extensive area for the passage, the absorption, is available. The means to develop a formulation for eye drops that is still drippable However, on the cornea of the eye already results in bioadhesive preparation, in which the effective ingredients stable and protected from microbial attack and out of it over an extensive tissue area Target organ can be absorbed.

The bioadhesive eye drops are to allow the active ingredients contained completely release their passage into the tissue and none enter into unwanted interactions with the biological tissue.  

Explanation of the essence of the invention

The invention has for its object to develop a method according to wel chem any active ingredients, but especially basic drugs, by the addition of a bioadhesive polymer, an acid and optionally isoto nisierend acting additives in a simple technology to eye drops processed can be. The bioadhesive eye drops are supposed to be on the cornea of the eye stick, cover as large an area as possible and contain additives that are toxic are logically harmless and favor the absorption of the active ingredients.

According to the invention, this object is achieved by the use of a polymer, an acid and optionally an isotonizing agent dissolved in a balanced Combined ratio to deliver a drippable drug form that is already bioadhesive itself and that is well spreading and sticking on the cornea of the eye.

As effective ingredients are all those drugs in question, for the one high bioavailability in the cornea or aqueous humor is desirable. At the same time, no determinations are made with regard to the impact quality. Insbeson dere should by the method according to the invention Antiglaucomatosa (for example certain β-receptor blockers) and other drugs (for example pilocarpine), which are to enter the aqueous humor of the eye, processed into eye drops that are good drippable. With respect to the polymer, no specifications met. In principle, all eye-compatible macromolecular substances (for example, polyvinyl alcohol, polyacrylic acid or polyacrylic acid esters), provided they have the required bioadhesivity. If the polymers over Hydroxyl groups should have shares of these freely. Unless the Containing polymeric carboxyl groups, these can be completely or partially neutralized his. In this case, preferably sodium, potassium, ammonium ions or ions organic amines used as counterions.

As acids that form ion pairs with the drugs, ver the eye tolerated amino acids and other acids in question at the respective pH of the Pharmaceutical form sufficiently dissociated, so that they as the ionic partner of the basic Drugs are eligible. In particular, in the eye drops amino acids (for example, proline, glutamic acid, arginine, glycine, tyrosine, methionine, histidine) as well as the relevant for stabilization reasons acids (for example, ascorbic, Amber, edetine, sorbic, o-phthalic, citric and orotic acid) as the ionic partner act.

Preferably, the invention is for producing drippable bioadhesive eyes drops. For certain reasons (even longer duration of action, sliding effect) can  However, it may be beneficial to use eye gels and eye ointments. This is easier Way possible by increasing the polymer content in the preparation.

embodiments

The following examples illustrate the invention in a nonlimiting manner.

Example 1

Aqueous eye drops with added acid A Drug (Atenolol) | 0.30 g B acid (ascorbic acid) 0.0880 g C water for injection too 100.0 g

The components A and B are dissolved in C. In the solution, the acid concentration is 5.0 mmol · 1 ^-1.

example 2

Aqueous eye drops with polymer additive A Drug (Atenolol) | 0.3 g D polymer (PVA) 4.5 g C water for injection too 100.0 g

Ingredient A is mixed with a bioadhesive mucus that forms when Component D in C is solved. In the chosen concentration of D is the Viscosity of the resulting solution 12. , , 15 mPa · s.

example 3

Aqueous eye drops with acid and polymer additives A Drug (Atenolol) | 0.3 g B acid (ascorbic acid) 0.0880 g D polymer (PVA) 4.5 g C water for injection too 100.0 g

Ingredients A and B are dissolved in a bioadhesive mucus that is formed when ingredient D in C is dissolved.  

example 4

Hydrophilic eye ointment with added acid A Drug (streptomycin, sulf.) | 0.1 g B acid (ascorbic acid) 0.0880 g D polymer (Eudispert) 8.0 g E sodium hydroxide solution (1 mol · 1 ^-1 ) 91.0 g

Ingredients A and B are mixed with a bioadhesive slime that forms when ingredient D. in E is solved. The mixture is homogenized.

example 5

Lipophilic eye ointment with added acid A drug | 0.1 g B acid 0.0880 g F ointment base 9.7 g

Ingredients A and B are mixed with F (mixture of 1.0 g cholesterol, 42.5 g viscous paraffin and white vaseline to 100.0 g). The mixture will then homogenized.

discussion

The drug is distributed from eye drops according to Example 1 in comparison to a "pure" aqueous solution better in favor of the cornea of the eye. The acids increase the partition coefficient, L, of the drug. Evidence for the better distribution was provided in vitro (distribution between n-octanol and Sörensen buffer pH 7.4) using the β-receptor blocker atenolol as an example. The distribution of atenolol from the eye drops with the acid was compared with the distribution of atenolol from a solution containing only water ( Figure 1). The distribution coefficients of atenolol from the acid-added eye drops are between 0.01 and 0.47. They differ significantly from the partition coefficient of a "pure" aqueous solution of atenolol (L = 0.009).

In addition, the permeation ability of the drug (determined ex vivo within 60 minutes with a perfusion apparatus on isolated pig eye corneas) is influenced by an addition of acid or polymer. The fastest possible permeates the drug from eye drops according to Example 1. The polymer additive (eye drops according to Example 2) inhibits the permeation. Nevertheless, even from eye drops according to Example 3, more drug permeates than from the "pure" aqueous solution ( Figure 2).

The bioadhesion of the eye drops according to Example 2 (determined ex vivo tensiometrically after a contact time of 0.5 minutes on a fresh pig intestine) is, depending on the type of polymer, between 8.00 and 439 Pa (see Table 1). Depending on the bioadhesion results in a prolonged residence time of the drug on the eye. The residence time of the drug was determined on the basis of naphazoline ex vivo on fresh pig eyes. The residence time of the eye drops with polymer was compared with the residence time of corresponding solutions that did not contain any polymer ( Fig. 3).

The drug is distributed from eye drops according to Example 3 better in favor of Cornea as from similar approaches without added acid. The proof of that better distribution was achieved in vivo by rabbit eye studies. The right eye of a rabbit was examined twice a day for 5 days with 1 Drops of the respective solution (see Table 2) dripped. The procedure was that Rabbits 1 and 2 with "pure" aqueous solution, rabbits 3 and 4 with eye drops according to Example 2, rabbits 5 and 6 were dropped with eye drops according to Example 3.

Tab. 3 shows the intraocular pressure (in vivo with a Tonometer according to Schioetz measured) of each eye summarized at the end of the experiment. The inner eye pressure of eyes dripped with acid-added eye drops (Example 3), differs significantly from the intraocular pressure of the eyes, which is characterized by a "pure" aqueous solution were dropped. A polymer additive (eye drops according to Example 2) Although also causes a reduction in intraocular pressure, but here are the Differences to the "pure" aqueous solution not significant. Because the intraocular pressure controlled by the β-receptors, must therefore from the eye drops with acid Addition (Example 3) more drug may be in the aqueous humor than from the "pure" aqueous solution.

The bioadhesion responsible for a long time lasting adherence of the respective eyes Pharmaceutical form (drippable solution according to Example 2 or 3, ointment according to Example 4) is responsible, is not affected by the addition of acid. The proof was administered ex vivo to eye drops according to Examples 4 and 5 as well as to various Model recipes (formulas 6 to 9) led. Bioadhesion of the gel (Example 4) and the ointment (Example 5) does not change by adding acid.  

model recipes

Table 1

Used mucilage concentration for the viscosity of 12 mPa · s, c, measured bioadhesion at this concentration, Δσ for the investigated mucilage

Table 2

Composition of Formulations 1-4, their distribution coefficients, L, and associated standard deviations, s _rel

Table 3

Measured intraocular pressure of animals treated with formulations 1-3 1-3 eyes

Claims (5)

1. A process for the preparation of bioadhesive eye drops, characterized in that the usual vehicle, water for injection, a water-swellable, bioadhesive polymer containing hydrophilic functional groups, preferably hydroxyl and / or carboxyl functions, an acid and if necessary an isotonizing admixed become. 2. A method for producing bioadhesive eye drops according to claim 1, characterized in that the concentration of the bioadhesive polymer in the Eye drops between 0.1 and 4.0%, but preferably between 1 and 3%, and that the hydrophilic functional groups of the polymer, as far as it is Hydroxyl groups, are free and / or, if they are carboxyl groups are completely or partially neutralized, preferably sodium, potassium, Ammonium ions or ions of organic amines act as counterions. 3. A method for producing bioadhesive eye drops according to claim 1 and 2, characterized in that the acid is a substance or a mixture of substances with a pKa between 1.5 and 6.5, preferably between 2.0 and 4.5 is used, which is capable of containing the basic in eye drops used basic Drugs to form ion pairs that penetrate more easily into the cornea of the eye can. 4. A method for producing bioadhesive eye drops according to claim 1 to 3, characterized in that in cases where the isotonicity of the dosage form is not alone can be secured by the contained drugs and excipients, in addition Isotonizing agent, preferably one for this purpose in pharmacy common ionic or nonionic excipient, for example sodium chloride, Sucrose, is used. 5. A method for producing bioadhesive eye drops according to claim 1 to 4, characterized in that in special cases, preferably to achieve a Slip effect, the concentrations of the polymer is increased to an extent that the Add eye drops to a gel or ointment.