HU198125B - Proess for producing pharmaceutical composition usable for otitis - Google Patents

Abstract

As the active ingredient of the present invention, the ear drops comprise the amino acid sulfhydryl group, preferably acetyl cysteine, pantetine or disulfiram, plus an aminoglycoside antibiotic or polymyxin B, as well as a steroidal anti-inflammatory agent, and optionally a keratolytic agent. L-cysteine is used. -1-

Description

The present invention relates to the preparation of pharmaceutical compositions for improving the condition of patients suffering from otitis media, especially chronic otitis media, and for restoring the middle ear to a healthy state.

Chronic otitis media is a disease that occurs in a relatively large percentage of the population, especially in adulthood but also in childhood. Early detection and correct treatment not only serve to avoid acute complications, but also to prevent later throat and deafness. In nearly one quarter of all hearing aids, hearing loss can be traced back to childhood otitlsckcrc, which is often associated with infectious diseases. Children who often suffer from otitis media also have a higher percentage of subacute and chronic otitis. Its main features include lack of tympanic membrane discontinuity, abdominal cavity lesions, recurrent outbreaks. In the general post-inflammatory reaction, local symptoms may be manifested or latent. These processes can lead to life-threatening complications if left untreated.

Mesothympanic chronic otitis is characterized by large and centrally located perforation of the ear, buccal mucous discharge and mucosal proliferation. Very easily develops bone damage or chronic mastoid. Typically, the cultivable microorganisms from the mucus belong to the genus Staphylococcus and Pseudomonas.

In epitimpanic chronic otitis, small and marginally located perforation, tympanic epithelial apoptosis, and lesser exudation, which is very dense, often purulent, and generally odorous. The corneal cortex of the auditory canal enters the tympanic cavity and takes the place of the mucous membrane there, and, due to the continuous peeling, the so-called epithelial cell mass. forms a pearl tumor. This dense mass destroys the bony structures of the tympanic cavity and can eventually lead to life-threatening complications. The inflammation in such cases is not only the process of mucous membranes but also the bone. This form of chronic otitis media is also characterized by superinfection.

Thus, in the cases listed above, chronic otitis is characterized by the fact that, due to a lack of peritoneal continuity, the tympanic cavity is exposed to the outside world and irreversible peritoneal damage occurs, which often results in severe hearing loss, which is associated with morbidity. As a result of inflammatory processes, the eardrum may be completely destroyed.

Early therapies for the treatment of this type of disease include ear drops containing boric acid, alcohol, hydrogen peroxide, silver nitrate, trichloroacetic acid, ultraseptil, balsam or chloramphenicol, which are only conditions for the treatment of symptoms and secondary infections. However, they have not been able to promote increased removal of mucus and pearl tumors and at the same time eliminate bacterial and fungal infections. Foreign preparations on the market are not suitable for this purpose. The use of Qtosporin branded ear drops for perforated eardrum is strongly contraindicated.

It is an object of the present invention to provide a process for the preparation of a pharmaceutical composition which has an adequate, mucolytic and / or keratolytic action on perforated peritoneum and which can suppress the action of infectious microorganisms such as bacteria and fungi.

It is a fundamental discovery of the process of the present invention that compounds having a sulfhydd1 moiety or moieties, due to their mucolytic and kerolyolytic activity, are successful in the treatment of patients with chronic otitis media, among other commonly known active substances.

The mucolytic effect of sulfhydryl-containing compounds in the treatment of respiratory diseases has been described in many forms. A number of pharmaceutical products are marketed with such active ingredients including Mucomyst, Mucolyticum Lappé, Fluimucil, Aibron, Acetein, Mueosoivin.

The use of sulfhydryl group compounds in reducing the viscosity of the inucus has thus been demonstrated in many cases, whether oral, topical or parenteral. The compound having a sulfhydryl group most commonly used acetylcysteine considering _LD50 values when administered orally - does satisfy these requirements.

dog LD ₅₀ 1000 mg / kg rat LD ₅₀ 6000 mg / kg mouse LD ₅₀ 3000 mg / kg

In the study of respiratory diseases, the implantation of bacterial flora becomes more difficult with the decrease of viscous viscosity, and it is very important to observe that in the presence of sulfhydride group compounds the bacteria show no encapsulation or other morphological changes.

The explanation for these phenomena lies in the mechanism of action of the thiol compounds, specifically in the exchange reaction, which is a proteolytic effect, as they separate peptide chains from one another.

The process of the present invention is based on the observation that, as with respiratory diseases, high-protein, high-protein, in most cases, supersaturated mucus is produced in the media of chronic otitis media, often unable to drain through the perforated membrane. In our experiments, it was surprisingly found that compounds containing a sulfhydryl group can rapidly and significantly reduce the viscosity of this type of mucus in vitro. For example, ear swabs from patients are liquefied in vitro in the presence of, for example, acetyl cysteine at pH 6.5-7.5.

Further experiments in which inflammation, superinfection and the

The incompatibility of the compounds with 198,125 compounds has been investigated, leading to the finding that compounds of different structure containing the sulfhydryl group can be combined with antibacterial, antifungal, non-specific anti-inflammatory and optionally keratolytic agents. Based on these, it has been found, in accordance with the observation described in the literature, that compounds containing a reactive sulfhydryl group may also react undesirably with aldehydes, epoxides, lactones and certain beta-lactams. [Eur. J. Respir. Dis. 61, Suppl., 111, 151-7 (1980)]. However, adsorption of certain antibiotics from the stomach is not adversely affected by compounds having a sulfhydryl group, in particular acetyl cysteine. These antibiotics include amoxicillin, doxycycline, or erythromycin. Eefalexin exhibits some but not significant retardation, but providing a relatively acidic pH may reduce the degree. Based on these, it was believed that conditions were present in which the sulfhydryl-containing compounds could be present in a formulation with the antibiotics listed.

M. F. Parry et. al. observed [J. Clin. Microbiol 5, 1, 58-61 (1977)], compounds containing a sulfhydryl group, in particular acetylcysteine, are capable of inhibiting the growth of certain Gram (+) and Gram (-) bacteria, including Pseudomonas aeruginosa. Under the test conditions used, acetyl cysteine exhibits synergistic activity in vitro with certain beta-lactams.

In the following, our studies have shown that N-acetyl-L-cysteine or its pharmacologically acceptable salts, such as the sodium, ammonium salt or zinc mercapide, have the best results, but have a mucolytic effect. also with compounds such as dithioerythrol, disulfiram, dimercaptosuccinate, glutathione, penicillamine or carbocysteine.

The use of chemotherapeutic agents commonly used in dermatological therapy may be used to combat bacterial infections due to inflammation. These include: neomycin, polymyxin 3, gentamicin, tobramycin, kanamycin, paromomycin, tetracyclines, chloramphenicol, nitrofurazone derivatives, thiOtricin, fusidic acid, amphomycin, penicillin derivatives and cephalosporin derivatives.

Among the commonly used anti-fungal chemotherapeutic agents for the treatment of co-fungal infections are: nistatin, amphotericin B, pimaricin, variotin, clotrimazole, miconazole, econazole, tolnaftat, cyclopyroxolamine, PVP-ampridine, methyl ester, benzyl benzoate, bicalastidine S, candicidin, cycloheximide, griseofulvin, haloprogin, miconazole nitrate, polyoxin D, pyrrole nitrine, sinefungin, thiabendazole, natamycin.

Synthetic corticoids, hydrocortisone, dexamethasone, fluoquinolone, fludroxycortide, cortisone acetate, triamcinolone acetonide, fluoroquinolone acetonide, mazipredone hydrochloride, be used as anti-inflammatory agents in the compositions of the present invention.

The most preferred dosage form of the pharmaceutical composition of the present invention having a secretolytic and chemo-rapcutic effect is the ear droplet. The eardrops easily penetrate areas where the dense, viscous mucus has accumulated and facilitate its removal relatively easily.

Most preferably, the secretolytic agent which has been found to be useful in our studies has a pH of 2.0 to 2.76 in a 1% aqueous solution of N-acctyl-L-cysteine. N-acetyl-L-cysteine, on the other hand, is capable of maximal viscosity reduction in the range of pH 6.0-8.0. If the pharmacologically acceptable salts of N-acetyl-L-cystine are used, the pH dependence is not so significant, but the degree of mucolytic effect on N-acetyl-L-cysteine is also lower. relative to [Am. Port. Respir. Dis. 90: 721-9 (1964)].

In the process of the present invention, agents having a litholytic (keratolytic) activity, preferably tretionine, salicylic acid and its derivatives, benzoic acid, resorcinol, may also be added.

At the Ear, Nose and Throat Clinic of the Medical University of Debrecen, we have investigated the types of pathogens found in chronic otitis media and often in the subacute otitis media in patients with adult and pediatric patients.

In our study, we analyzed the ear secretions of 510 patients for bacterial infection. Our results are shown in Tables 1, 2 and 3.

Table 1

Occurrence rate of pathogens in child material

Pathogen Number of cases Case% Staphylococcus aureus 92 32.97 Staphylococcus epidermidis 40 14.33 Pseudomonas aeruginosa 33 11.82 Escherichia Coli 28 10.03. Pseudomonas sp. 17 6.09 Klebsiella sp. 17 6.09 Proteus sp. 11 3.94 Bacillus sp. 8 2.86 Streptococcus faecalis 7 2.50 Streptococcus pneumoniae 6 2.15 Streptococcus alpha- haemolytic 6 2.15 Streptococcus beta haemolytic 5 1.79 Escherichia alkal.-dispar 4 1.43 Haemophylus sp. 3 1.07 AlcaJigenes faecalis 1 0.35 Acinetobacter 1 0.35 279 100

198 125

Table 2

Occurrence rates of pathogens in adult material

pathogens Number of cases Case% Staphylococcus aureus 72 31.16 Pseudomonas aeruginosa 45 19.48 Staphylococcus epidermidis 31 13.41 Pseudomonas sp. 22 9.52 Proteus sp. 21 9.09 Streptococcus alpha- haemolytic 8 3.46 Klebsiella sp. 6 2.59 Bacillus sp. 5 2.16 Streptococcus beta haemolytic 5 2.16 Escherichia alkal.-dispar 4 1.73 Streptococcus faecalis 4 1.73 Escherichia coli 3 1.29 Ilacmophylus sp. 2 0.86 Acinetobacter sp. 2 0.86 Streptococcus pneumoniae 1 0.43 Alcaligenes faecalis 0 0 231 100

Table 3

Occurrence rate of pathogens, total material

pathogens Number of cases Case% 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- haemolytic 14 2.74 Bacillus sp. 13 2.54 Streptocöccus faecalis 11 2.15 Streptococcus beta haemolytic 10 1.96 Escherichia alkal.-dispar 8 1.56 Streptococcus pneumoniae 7 1.37 Haemophylus sp. 5 0.98 Acinetobacter sp. 3 0.58 Alcaligenes faecalis 1 0.19 510 100

Table 4

agent 0 R M E 11 neonácin 465 5 13 27 88.9 tobramycin 247. 61 86 116 79.2 oxacillin 22'9 77 13 191 72.6 methicillin 242 95 27 146 64.6 carbenicillln (pyopen) 260 91 22 137 63.6 gentainicin 255 118 72 65 53.7 cephaloride (ceporin) 131 182 27 170 51.9 streptomycin 342 87 42 39 48.2 Polymycin B 330 103 8 69 42.7 ainpicillin 307 120 11 72 40.8 oleandomycin 213 179 4 114 39.7 klorocid 196 197 11 106 37.2 suinetrolim 99 259 12 140 36.9 eritroinicin 183 208 6 113 36.4 penicillin 203 218 22 67 29.4 tetracycline 136 279 16 79 25.4 all examination: 510

Explanation of symbols used in the table:

= number of untested cases R = ineffective (resistant)

M = moderate effect E = therapeutic effect (sensitive)

H = efficacy (%)

The fungal species found in the ear secretions were not examined at depths similar to the bacterial flora, but it was found, in accordance with literature data, that the most characteristic species:

Aspergillus flavus

Aspergillus fumigatus

Aspergillus niger

Candida albicans

We would like to present our results by way of examples, without limiting our claims to protection.

Example 1 (microcrystalline suspension) Composition:

N-acetyl L-cysteine 500 mg tobramycin sulfate 100 mg hydrocortisone acetate 100 mg (microcrystalline) neomycin sulfate 100 mg aqueous propylene glycol solution 10.0 ml

As shown in the tables, there is significant agreement between bacterial infections observed in pediatric and adult patients with otitis media. The most common bacteria are Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus epidermidis.

The results of the treatment of secretions with antibacterial agents are summarized below:

Example 2 (solution) • composition:

N-acetyl-L-cysteine 500 mg tobrinicin sulfate 100 mg mazipredone chloride 50 mg neomycin sulfate 100 mg propylene glycol aqueous solution 10.0 ml

-4198 125

500 mg

100,000 IE

100 mg mg ad 10.0 ml

Example 3 Composition:

N-Acetyl-L-Clistol Polymyxin B-Sulfal Neomycin Sulfate Razazedredone Chloride Propylene Glycol Aqueous Solution

Example 4

Ingredients:

disulfiram salicylic acid polymyxin B sulfate neomycin sulfate hydrocortisone acetate propylene glycol aqueous solution

Example 5 Composition:

pantethine benzoic acid polymyxin B sulfate neomycin sulfate beclometazone dipropionate propylene glycol aqueous solution

Example 6 Composition:

N-Acetyl L-cysteine tobramieln sulfate hydrocortisone acetate (microcrystalline) propylene glycol aqueous solution

Example 7 Composition:

N-acetyl L-cysteine neomycin sulphate mazipredone chloride propylene glycol aqueous solution

Example 8 Composition:

N-acetyl L-cysteine tobramycin sulfate triamcinolone acetonide benzoic acid propylene glycol aqueous solution

Example 9 Composition:

N-acetyl L-cysteine tobramycin sulfate hydrocortisone acetate (microcrystalline) propylene glycol aqueous solution

500 mg 500 mg 100.000 IE 100 mg 100 mg ad 10.0 ml

450 mg 100 mg 100.000 IE 100 mg 100 mg ad 10.0 ml

850 mg 100 mg 100 mg ad 10.0 ml

1100 mg

100 mg 60 mg ad 10.0 ml

Example 10 Composition:

N-acetyl-L-cysteine 5 tobramycin sulfate nasipredone chloride propylene glycol aqueous solution, Example 11

1 «J

Ingredients:

N-acetyl L-cysteine tobramycin sulfate dcxamethazone sodium phosphate propylene glycol aqueous solution

Example 12 Composition:

you

N-acyl-L-cystic polymyxin B sulfate tobramycin sulfate prednisolone sodium succinate propylene glycol aqueous solution

Example 13 Composition:

3θ Disulfiram Salicylic Acid Polymyxin B Sulfate Gentamicin Sulfate Dexamachine Sodium Phosphate Propylene Glycol Aqueous Solution

Example 14 Composition:

pantethylene benzoic acid polymyxin B sulfate tobramycin sulfate betamethasone disodium phosphate propylene glycol aqueous solution

600 mg 125 mg mg ad 10.0 ml

550 mg 125 mg mg ad 10.0 ml

700 mg 100,000 IU 125 mg mg ad 10.0 ml

500 mg 500 mg 100,000 IU 100 mg mg ad 10.0 ml

450 mg 100 mg 100.000 IU 100 mg mg ad 10.0 ml

600 mg 100 mg 40 mg 120 mg ad 10.0 ml

500 mg 125 mg 100 mg ad 10.0 ml

Claims (4)

PATENT CLAIMS A process for the preparation of an ear drop composition 50 characterized in that amino acids containing from 3% to 19% by weight, preferably from 5% to 15% by weight, of the sulfhydryl group are preferably acetyl cysteine or its pharmacologically acceptable salts or pantethine or disulfiram and 0.01 to 6.00% by weight, preferably 0.1 to 3.0% by weight of an aminoglycoside antibiotic or polymyxin B, and 0.01 to 5.00% by weight of steroidal anti-inflammatory drugs and optionally 1 to 11% by weight of keratolytic aromatic acid alone in a known manner, in combination with excipients and carriers commonly used in physiological aces. Process according to claim 1, characterized in that the acetyl cysteine is preferably N-acetyl-L65 eistein. -5nate, triamcinolone acetonide, dexamicol sodium phosphate, prednisolone sodium succinate or betamethasone disodium phosphate are used. The method of claim 1, wherein 5 using a salicylic acid or a benzoic acid as a keratolytic aromatic acid. 15.1.1981 3. The method of claim 1 wherein the aminoglycoside antibiotic is tobramycin or neomycin or a pharmacologically acceptable salt thereof. 4. The method of claim 1, wherein the steroidal anti-inflammatory agent is mazipredone chloride, hydrocortisone acetate, beclomethasone dipropio.