CS273281B1 - Auricular drops and method of their preparation - Google Patents

Abstract

Ear drops containing from 3 to 19 weight percent, or to advantage from 5 to 15 weight percent of amino acid that contains thiol-group, to advantage cysteine or its pharmaceutically acceptable salts or pantotheine or disulfiram, from 0.01 to 6.00 percent, to advantage 0.1 to 3.0 percent of antibiotic agent of aminoglycoside type or polymyxin B, from 0.01 to 5.00 percent of anti-inflammation agent of steroid type and eventually from 1 to 11 percent of keratolytically efficient aromatic acids together with additives and carriers used in otology for ear drops.

Description

(54)

Ear drops and their preparation

57) Ear drops comprising 3 to 19%, preferably 5 to 15%, of an amino acid comprising a thiol group, preferably cysteine, or a pharmaceutically acceptable salt thereof, or pantotheine or disulfiram, 0.01 to 6.00%, preferably 0, 1 to 3.0% of an aminoglycoside type antibiotic or polymyxin B, 0.01 to 5.00% of an anti-inflammatory agent of the steroid type, and optionally 1 to 11% of keratolytically active aromatic acids, together with additives and carriers used in otology for ear drops.

CS 273281 Bl

CS 273281 Bl

The present invention relates to novel pharmaceutical compositions suitable for improving the condition of patients suffering from external otitis or otitis media, particularly chronic otitis media, as well as improving the health of the middle ear.

Another aspect of the invention is a process for preparing a novel formulation.

Chronic otitis is a disease that occurs in both adulthood and childhood, and suffers from a relatively high percentage of the population. Not only acute complications, but also bradyakusi (hearing disorders) and subsequent permanent hearing disorders later can be avoided by early diagnosis and appropriate therapy. Hearing impairment of about 1/4 of all patients suffering from these conditions may be associated with inflammation that persists in a confined space and often develops in connection with infectious diseases. Both subacute and chronic otitis are often detected in children who often suffer from them. The basic characteristics of these diseases are: eardrum discontinuity, tympanic cavity changes and their recurring symptoms. In addition to these general inflammatory reactions, local symptoms may be manifest or latent. If therapy is missed, these symptoms can lead to life-threatening complications.

Mesotympanic chronic otitis is characterized by large central perforation of the tympanic membrane with mucus discharge and mucus proliferation. Bone damage and chronic mastoitis can easily develop. Staphylococcus and Pseudomonas are microorganisms that can be easily cultivated from effluent.

Smaller and marginal perforation as well as tympanic epithelial metaplasia and lower discharge range are characteristic of epitympanic chronic otitis: the discharge is very dense, often purulent and smelly. The keratinizing area of the entrance passage epithelium penetrates into the tympanic cavity, replacing the mucoid membrane that acts under normal conditions and, due to constant separation, forms an epithelial mass of cells called cholesteatoma. This strong mass suppresses bone formation in the tympanic cavity and may eventually lead to life-threatening complications. Inflammation in these cases not only affects the mucoid membrane, but also extends to the bone. Superinfection is also characteristic of this form of chronic otitis.

Characteristic features of chronic otitis in these cases include tympanic discontinuities, causing the tympanic cavity to have free contact with the external environment and can thus easily cause pathological processes and irreversible tympanic damage, causing severe hearing defects that increase with duration diseases. In addition, the eardrum can be completely removed as a result of inflammatory processes.

Ear drops containing boric acid, alcohol, silver nitrate, trichloroacetic acid, ultraseptyl, balms or chloramphenicol have previously been proposed for the treatment of these diseases. These ear drops were suitable for symptomatic treatment and for the relief of symptoms of secondary superinfection, but were not able to remove discharge or cholesteatoma and prevent bacterial and fungal infections. Further, no commercially available preparation is currently known to be suitable for altering the consistency of the ear outflow and thus to facilitate the outflow or removal from the ear. Often, otological preparations are reported which cannot be used for an open tympanic cavity.

Generally known combinations preferably comprise an aminoglycoside antibiotic together with a non-specific anti-inflammatory agent. Despite the possible synergistic effect, these combinations are unable to cure the complex of ear diseases, although in certain cases they may prevent the further spread of bacterial infections and chronic inflammation; however, due to their composition, they are not capable of inducing simultaneous removal of the effluent, except for its above-mentioned treatment. This is especially necessary when monitoring the etiology of otitis.

Based on this knowledge, it is an object of the present invention to provide compositions which exhibit a sufficient mucolytic and / or keratolytic effect in the case of a perforated drum and are capable of suppressing the destructive effects of bacteria and fungi.

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The invention is based on the surprising recognition that, due to its mucolytic and keratolytic effects, thiol-group-containing compounds can be successfully used in conjunction with other generally known drugs in the treatment of patients suffering from chronic otitis. The mucolytic effect of thiol-containing compounds for the treatment of respiratory diseases has been described in several forms. Many forms of formulations containing these active ingredients such as Mucomyst, Mucolyticum Lappe, Fluimucil, Aibrom, Acetein and Muoosolvine are commercially available.

The utility of thiol-group-containing compounds for reducing mucus viscosity has been tested in many cases by both local and oral or parenteral administration. One of the most commonly used thiol-containing compounds is acetylcysteine satisfying the requirements of oral administration based on its Βϋ, -θ values:

LDj-θ in dogs = 1000 mg / kg body weight

LD ≥ q in rats = 6000 mg / kg body weight

LDg in mice = 3000 mg / kg body weight.

In respiratory diseases, the implantation of bacterial flora becomes more difficult as the mucus viscosity decreases. According to another important observation, the bacteria are not encapsulated or morphologically altered in the presence of compounds containing a thiol group.

This observation can be explained by the effect of the thiol-containing compounds in more detail by an exchange reaction resulting in separation of the peptide chains.

The invention is based on the observation that, like in respiratory diseases, a highly viscous superinfected discharge is formed in most patients with otitis media, which is often unable to flow, even with a perforated tympanic membrane. Surprisingly, it has been found during the investigation that, in a suitable environment, compounds containing thiol group (s) are able to reduce the viscosity of these types of effluents in vitro quickly and significantly. In the presence of thiol-group-containing compounds, for example, various acylcysteines at pH 6.7 to 7.5, in vitro patient outflows become liquid within a short time.

In a further investigation, which included cases of inflammation and superinfection, thiol-group compounds of various structures were combined with antibacterial non-specific, anti-inflammatory and possibly keratolytic drugs. In line with previous observations, it has been found that, in the case of several combinations, compounds containing reactive thiol groups are capable of participating in an adverse reaction with certain aldehydes, epoxides, lactones and beta-lactams (EUr. J. Respir. Dis. 61, Suppl. 11). , pp. 151-157 (1980)). However, the absorption of some antibiotics from the stomach is not adversely affected by thiol-containing compounds, in particular acetylcysteine. Such antibiotics include, but are not limited to, amixicillin, tobramycin, doxycycline, neomycin, and erythromycin. Some, but not significant extent of retardation can be observed with cephalexin; however, by providing a relatively acidic pH, this effect can be reduced. Based on these findings, it appears possible to provide conditions where the thiol-containing compounds are present in a stable mixture together with the above-mentioned types of antibiotics.

According to observations by M. F. Parry et al. (J. Clin. Microbiol. 5, 58-61, 1977) compounds containing a thiol group, particularly acylcysteines, are capable of inhibiting the growth of some Gram-positive and Gram-negative bacteria such as Pseudomonas aeruginosa. Under certain experimental conditions, acetylcysteine shows a synergistic effect with some antibiotics under in vitro conditions.

Further research has resulted in N-acetyl-L-cysteines and their pharmaceutically acceptable salts such as sodium or ammonium salt or zinc, mercaptide salt giving the best results among the thiol-containing compounds; however, other compounds such as dithioerythritol, disulfiram, dimercaptosuccinate, glutahione, pantothein or carbocysteine may also exhibit a mucolytic effect.

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Acetylcysteine, especially N-acetyl-L-cysteine, which has been found to be the most suitable mucolytic agent, has been found to have a pH of from 2.0 to 2.76 in aqueous solution at 1% concentration. N-acetyl-L-cysteine has the highest viscosity-reducing effect at a pH in the range of 6.0 to 8.0. When used in the form of their pharmaceutically acceptable salts, the pH dependence is not so significant, but the mucolytic effect of the salts is lower than N-acetyl-L-cysteine (Am. Rev. Respir. Dis. 90, 721-719 / 1964 /).

Antibacterial chemotherapeutics commonly used in dermatological therapy may be used to control bacterial infections occurring in inflammation. Such drugs are, for example, neomycin, polymyxin B, gentamycin, tobramycin, paromomycin, tetracyclines, chloramphenicol, nitrofurazone derivatives, tyrothricin, furidic acid, amphomycin, penicillins and cephalosporins as well as therapeutically useful derivatives of these compounds.

Steroids, synthetic corticoids such as hydrocortisone, dexamethasone, fluocinolone, fluodroxycorticoid, cortisone acetate, triamcinolone acetonide, fluocinolone acetonide, mazipredone hydrochloride and beclomethasone dipropionate are preferably used as anti-inflammatory agents in the compositions of the invention.

The compositions of the invention may optionally also contain desquamating agents such as tretinoin, salicylic acid or derivatives thereof, also such as benzoic acid and resorcinol. The compounds of interest are usually capable of effectively removing flat epithelial penetration into the tympanic cavity or cholesteatoma.

The most preferred formulations of the mucolytic and chemotherapeutic compositions of the present invention are, in particular, ear drops having a liquid consistency readily penetrating sites where dense and viscous effluents accumulate and promote relatively easy removal thereof.

The ear drops according to the present invention comprise by weight of the composition. 3 to 19%, preferably 5 to 15% of an amino acid containing a thiol group, preferably acetylcysteine, or a pharmaceutically acceptable salt thereof, or pantotheine or disulfiram, 0.01 to 6.00%, preferably 0.1 to 3.00%, antibiotics of aminoglycoside type or polymyxin B, 0.01 to 5.00% of an anti-inflammatory agent of the steroid type and optionally 1 to 11% of keratolytic aromatic acids together with additives and carriers used in otology for ear drops.

However, the following was found in the therapeutic evaluation of ear drops according to the above composition.

In the case of external diffuse eczematic otitis (otitis externa diffusa ekzematosa) the result was very favorable: Improvement or recovery was observed in about 86% of patients. Further, most of the improved cases could be completely cured by the following drying treatment procedure.

In the case of chronic cholesteatoma, chronic cholesteatoma otitis (otitis media chronica cholesteatomatosa), it was observed that the mass of cholesteatoma was more easily removable by otological aspiration treatment than in untreated cases.

During the therapeutic study of the formulations of the invention, no pathological process progress was observed in any way, no side effects that could motivate discontinuation of treatment occurred.

Using the compositions of the invention, the recovery time was so reduced that the pathological condition was improved more rapidly. That is, most importantly, after use of the composition according to the invention, the amount of ear discharge was suddenly reduced and its consistency was preferably changed. In general, the ear outflow did not become more fluid, but its viscosity was reduced by some precipitation. No increase in discharge was observed.

Several formulations of the invention have also been studied, with one active formulation compound being omitted to promote the progressive nature of the multi-component formulation of the invention. These experiments led to the following results.

CS 273281 Bl

The use of a 1% tobramycin solution resulted in a significant improvement in pathological processes in about 60% of patients suffering from chronic mesotympanic otitis; this ratio did not exceed 40% in patients suffering from external otitis.

When only steroids were administered, the majority of patients showed subjective improvement, but the objective improvement was not convincing. Objective improvements were observed only in those cases involving major tympanic damage, severe hyperemia and significant mucosal membrane hypertrophy of tympanic cavity as well as in cases of external eczematic otitis (otitis externa eczematosis).

Surprisingly, it has been found that aqueous solutions (pH 7.0 + 0.2) containing 3 to 19%, preferably 5 to 15% of compounds containing thiol groups such as acetylcysteines, preferably N-acetyl-L-cysteine, preferably affect viscosity and at the same time they also affect inflammatory procedures. Dilution of the effluent in this application was not observed, however, the effluent was somewhat reduced due to a decrease in its viscosity. The outflow, which had a coherent and slimy character, rather changed to a precipitated form in the treatment procedure.

In the Department for Otorhinolaryngology at the University of Medicine in Debrecen, both adult and pediatric patients were investigated for the composition of pathogenic microorganisms appearing in the outflows of patients suffering from chronic otitis media (otitis media chronica ,; analyzed 510 outflows per type of bacterial infection). 279 children and 231 adults are summarized in Table 1.

TABLE 1

FREQUENCY OF PATHOGENIC MICRO-ORGANISMS

Pathogen Number of cases % of cases Staphylococcus aureus 164 32.15 Pseudomonas aeruginosa 78 15.29 Staphylococcus epidermidis 71 13.92 Pseudomonas sp. 39 7.64 Proteus sp. 32 6.27 Escherichia coli 31 6.07 Klebsiella sp. 23 4/5 Streptococcus alpha-haemolyticus 14 2.74 Bacillus sp. 13 2.54 Stréptococcus faecalis 11 2.15 Streptococcus beta-haemolyticus 10 1.96 Escherichia alkal.dispar 8 1.56 Stréptococcus pneumoniae 7 1.37 Haemophylus sp. 5 0.98 Acinetobacter sp. 3 0.58 Alcaligenes faecalis 1 0.19 510 100.00

Observations have shown that there is an important consensus of bacterial infections in both adult and pediatric patients. As is evident from Table 1, the most commonly occurring pathogens are Staphylococcus aureus, Pseudomonas aeruginosa and Staphylococcus epidermidis.

Furthermore, Table 2 shows the results of treatment of efflux with antibacterial agents.

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TABLE 2

Active ingredient 0 R M AND Act. neomycin 465 5 13 27 Mar: 88.9 tobramycin 247 61 86 116 79.2 oxacillin 229 77 13 191 72.6 methicillin 242 95 27 Mar: 146 64.6 carbenicillin 260 91 22nd 137 63.6 cephaloridine 131 182 27 Mar: 170 51.9 gentamycin 255 118 72 65 53.7 streptomycin 342 87 42 39 48.2 polymyxin B 330 103 8 69 42.7 ampicillin 307 120 11 72 40.8 oleandomycin 213 179 4 114 39.7 chloramphenicol 196 197 11 106 37.2 Co-trimoxazole 99 257 12 140 36.9 erythromycin 183 208 6 113 36.4 penicillin 203 218 22nd 67 29.4 tetracycline 136 279 16 79 25.4

total attempts: 510

Claims (1)

Symbols used in Table 2: 0 = number of unrated cases R = inactive (resistant) M = average effective A ”therapeutically effective (sensitive) act. = efficiency% In assessing the occurrence of fungi occurring in the ear outlet, it has been found, in accordance with the literature, that the most frequently occurring and characteristic are Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger and Candida albicans. Ear drops of the invention are prepared as follows. About half of the required amount of propylene glycol is added to the bulk of the required amount of water, and then, in order, the thiol group-containing compound, which is preferably completely soluble or capable of forming a microcrystalline suspension, is added first. After a possible solution clarification, zinc oxide is added, which can be dissolved with stirring for up to 1 hour. Zinc oxide is used to stabilize thiol compounds. Thereafter, the pH of the solution or suspension is adjusted by the addition of preferably sodium hydroxide and then an antibacterial additive suitably selected from the group of aminoglycosides is introduced. After addition of the second half of propylene glycol, an anti-inflammatory agent is added, maintaining the pH at 7.0 ± 0.1 by small additions of 1M sodium hydroxide solution. In any case, complete dissolution is not required when the anti-inflammatory agent is introduced. Sometimes microcrystalline suspensions are prepared. After introduction of the anti-inflammatory agent, additional excipients are added and, if necessary, the solution is filtered and in any case processed into a sterile form. The compositions and procedures of the present invention are illustrated in more detail by the following non-limiting examples. CS 273281 Bl Example 1 Preparation of a microcrystalline suspension N-acetyl-L-cysteine 500 mg tobramycin sulfate 100 mg Hydrocortisone acetate (microcrystalline lický) 100 mg neomycin sulfate 100 mg aqueous solution of propylene glycol to 10,0 ml Example 2 Preparation of the solution Folders: N-acetyl-L-cysteine 500 mg tobramycin sulfate 100 mg mazipredone hydrochloride 50 mg neomycin sulfate 100 mg aqueous solution of propylene glycol to 10,0 ml Example 3 Components: N-acetyl-L-cysteine 500 mg polymyxin B sulfate 100 000 IU neomycin sulfate 100 mg mazipredone hydrochloride 50 mg aqueous solution of propylene glycol to 10,0 ml Example 4 Components: disulfiram 500 mg salicylic acid 500 mg polymyxin B sulfate 100 000 IU neomycin sulfate 100 mg hydrocortisone acetate 100 mg aqueous solution of propylene glycol to 10,0 ml Example 5 Components: pantothein 450 mg benzoic acid 100 mg polymyxin B sulfate 100 000 IU neomycin sulfate 100 mg beclúmethasone dipropionate 10 0 mg aqueous solution of propylene glycol to 10,0 ml