HU213508B - Process for producing pharmaceutical compositions for treating piogene and athopic leather diseases - Google Patents

Abstract

The present invention relates to a method for the preparation of a pharmaceutical composition comprising at least one lysate of at least one of the cultures of bacterial cultures of Haemophilus influenzae, Diplococcus pneumoniae, Klebsiella pneumoniae and ozaneae, Staphylococcus aureus, Streptococcus pyogenes, Streptococcus viridans, and Neisseria catarrhalis together with at least one pharmaceutically acceptable additive. and is converted into a pharmaceutical composition for the treatment of atopic skin diseases. EN 213 508 B Description Scope Page (Including 1 Tab Figure)

Description

FIELD OF THE INVENTION The present invention relates to a method of treating dermatological diseases comprising as active ingredient Haemophilus influenzae, Diplococcus pneumoniae, Klebsiella pneumoniae and ozaneae, Staphylococcus aureus, Streptococcus pyogenes, Streptococcus viridans, and at least three bacteria of Neisseria catarrhalis.

Skin diseases caused by purulent bacteria are still a significant part of the dermatological patient population. On the one hand, due to the characteristic symptoms of the disease, and due to the epidemiological background, the pyoderma patient is considered infectious, the child cannot enter the community and the adult becomes incapacitated for more or less time.

Piogenic diseases are one of the well-differentiated classical skin diseases. Both their topical and systemic antibacterial treatments are clear, yet their incidence is frequent, in many cases the protracted nature of the healing process and the high number of relapses. In cases of prolonged cure and often recurring chronic conditions, in addition to environmental predisposing factors, dysfunction of the immune system must be considered.

In addition to the large number of pyogenic skin diseases, 3-10% of the population has atopic or prone to atopic disease (spontaneous allergy caused by unknown allergens). The disease can be very long-lasting and frustrate both the patient and the doctor.

In spite of the usual daily treatments, influencing the disease does not produce sufficient therapeutic results. In the current dermatological literature, this polysymptomatic disease (eczema infantum, endogenous eczema, prurigo, constitutional neurodermitis) is widely known.

It is well known that relapse of the upper respiratory tract is associated with the exacerbation of skin symptoms in atopic patients. The disease is characterized by congenital predisposing, often recurrent, dehydrated dermatitis, which is associated with increased IpE formation and a number of constitutional symptoms (Turkish E. Pediatric Medicine, Budapest, 1987, p. 35).

A large group of allergic vasculitis is also a therapeutically problematic dermatologic disorder. They occur in different clinical forms. The etiology and pathogenesis of the process, which is localized to the skin and less frequently to the internal organs, is unclear. Different causes cause different types of vasculitis (vasculitis). All of this is in favor of an immune origin (Gy. Petrányi, Autoimmune Diseases, Akadémiai Kiadó, Budapest, 1974).

The skin process can be associated with mild or severe, life-threatening internal organ damage and has a high incidence of relapse. Its treatment is borderline within the dermatology and internal medicine field. In the event of complications, consideration should be given to a history of infectious, systemic or autoimmune disease, bacterial foci, or resolution.

In the therapeutic practice there is little known systemic formulation or active ingredient for the proper treatment of skin diseases. Most known formulations usually have a very long duration of action (several weeks or months), which is often transient and often has side effects.

It has therefore been an object of the present invention to provide a composition that can effectively treat the above skin conditions and thereby reduce the dosage of other drugs.

Another aim was to reduce the recurrence rate of recurrent pyogenic skin diseases.

A further aim was to reduce the time required for treatment.

It is a further object of the present invention to provide a natural immunostimulant formulation having the same efficacy as synthetic immunostimulant formulations used in dermatology, but having no adverse health effects.

Surprisingly, it has been found that especially chronic and acute pyogenic skin diseases and atopic dermatitis can be effectively treated with Haemophilus influenzae, Diplococcus pneumoniae, Klebsiella pneumoniae and ozaneae, Staphylococcus aureus streptococcus pyogenes, Streptococcal viridia, Streptococci

The present invention therefore relates to a method of treating pyogenic and atopic skin diseases comprising Haemophilus influenzae, Diplococcus pneumoniae, Klebsiella pneumoniae and ozaneae, Staphylococcus aureus, Streptococcus pyogenes, Streptococcus viridans, and Neissaria,

Preferably, the pharmaceutical composition is prepared from bacterial cultures of Staphylococcus aureus, Streptococcus pyogenes and Streptococcus viridans.

Of course, the active ingredients are not limited to the three bacteria mentioned above; any combination of 3-8 of the above bacteria is effective.

The active ingredient of the composition according to the invention may be prepared according to the Hungarian patent specification No. 180,005 or by methods known in the art.

Haemophilus influenzae, Diplococcus pneumoniae, Klebsiella pneumoniae and ozaneae, Staphylococcus aureus, Streptococcus pyogenes and viridans, and Neisseria catarrhalis lysate (recommended in 7mg and 3.5mg pediatric capsules) are BronchoVaxom an immunobiostimulant in the form of adjuvant and preventive therapy. It is not suitable as monotherapy for the treatment of an already established disease, according to previous studies.

Extensive study of the mechanism of action of the drug has shown that it is able to significantly increase the number of macrophages in the mucous membranes of the respiratory tract and of the digestive tract and to increase phagocytosis (Fontanges, R .: Study of the stimulation of peritoneal macrophages by an anti -bronchotic lisate, Untersuchungsbericht, 1982: Manuel, J.:

HU 213 508 Β

Untersuchungsbericht, 1987.). The composition increases the number of T lymphocytes (Clot, J., et al., Traitement pairs of Broncho-Vaxom des infections respiratory resections; treatment of chronic bronchitis, 5th Congress of SEP, Paris, Sept. 1986), promotes T lymphocyte responsiveness and outperforms the response induced by synthetic immunostimulants, and positively influences the Thelper / T suppressor ratio.

Respiratory immune stimulation is only expected after several weeks or months of treatment when taking the product (Copová, M., et al. and the result shows moderate significance only with a certain fraction of immunoglobulins (IgD). Based on this, it can only be used as an adjunctive therapy for the prevention of respiratory disease, it has no therapeutic effect on its own, and less than 50% of patients treated with acute disease have shown therapeutic benefit (reduction of antibiotic use, school absenteeism). decrease, etc.). In acute upper respiratory tract disease, no significant difference was observed between adjuvanted and non-adjuvanted patients (Broncho-Vaxom prospectus, Biogal).

When used in the treatment of skin diseases, the compositions of the present invention and the above composition are found to have a significant effect in contrast to the treatment of respiratory diseases.

Compared to the effect of Broncho-Vaxom on respiratory diseases, it had a significant therapeutic effect on skin diseases after 48 hours (eg furunculus) but was effective in all cases within 7 days (eg stinging).

Accordingly, the compositions of the present invention are useful not only as adjuvant therapy but also as a causal therapist for the treatment of pyogenic and atopic skin diseases, and exhibit a significant effect attributable solely to the administration of the composition (as opposed to respiratory disease) and respiratory disease. in comparison, the effect of piogene on skin diseases is significantly shorter.

These results were not predictable given the original effect of the bacterial lysates used as components of the composition of the invention. The results of therapy with the compositions of the invention are at least equivalent to those of conventional topical or systemic methods, but are generally superior. Of course, the compositions of the invention may also be combined with conventional therapeutic methods.

Synthetic immunomodulators have a drastic effect on the body's defense mechanism, their effect is questionable, and in many cases they cause serious side effects. The compositions of the present invention are the first dermatological immune drugs containing natural substances and thus have the advantageous effects of synthetic formulations used in similar fields without their side effects.

The amount and quality of bacterial lysates in the compositions of the invention may vary depending on the subject being treated, the pathogen, the severity of the disease, the age and condition of the subject being treated, and the like.

The daily dosage of the compositions of the invention is generally 0.05 to 5 mg / kg body weight; of course, you can deviate upwards and downwards from this range.

Experiments were conducted under clinical conditions to test the compositions of the invention. Although it has been shown in our preliminary studies that there is a wide variety of therapeutic uses, the compositions of the invention have been used, for simplicity, in the commercially available Broncho-Vaxom (BV) formulation as described below.

BV was used in five types of disease in the pyoderma group: impetigo, folliculitis, furunculus, erysipelas, hydradenitis axillaris. Children under the age of 14 were given the capsule for children, and over the age of 14 the adult capsule was given. Based on the course of the disease, 88 cases of acute pyogenic episodes were used as adjuvant therapy, and 28 cases were used as monotherapy in four disease groups (Table 1).

A total of 116 patients were taken for BV, with the youngest being 2 years old and the oldest being 73 years old. BV was administered according to the analogy to a well-established dosing regimen for respiratory tract infections (Weiss, S: 5 ^, Congress of SEP, Paris, Sept. 1986).

Study I

In acute illness, one capsule was taken daily in the morning from the day of application until the symptoms disappeared, but for at least 10 days. In this group of diseases, topical and / or systemic antibacterial therapy was routinely used in routine dermatological practice in combination with BV. Given the individual course of the five forms, the patient was considered cured if:

a) as a child he / she was able to return to the community of children (kindergarten, kindergarten, school),

(b) has regained the patient's earning capacity in working adults,

(c) in "non-working" adults, when the classic symptoms of the disease have disappeared.

The patient was considered cured of the disease symptom when:

furunculus group: fever, edema, no pain, necrotized follicular and perifollicular tissue, no epithelial deficiency;

in folliculitis group: the wart is emptied, there is no bloody yard, no epithelium;

erysipelas group: no fever, no pain, no edema, no complications;

HU 213 508 Β in impetigo group: no roast, wetted, epithelial area;

in the hydradenitis group: no pain, cutaneous, subcutaneous nodule softened, smoothed or emptied (8).

In each case, the duration of the recovery was recorded and compared with the average recovery time of a patient of the same diagnosis from a previous year (1986) at the Karcag Institute for Skin and Gender Care who had not taken BV. In the control group, only those cases were recorded for which the first application date and the end date of treatment were accurately recorded on the patient card. This represented the average healing data for our caregiver in 1986 (Table 2).

Statistical calculations were performed on an IBM AT compatible machine by DATE Research Institute (Karcag). Significance was determined by multivariate linear regression calculation based on the F value obtained.

II. test

In the chronic or prolonged disease group, 1 capsule was administered daily for 10 days during the first month of treatment, and after 20 days in the second and third months, the patient received 1 capsule daily for another 10 days. Only adult patients with recurrent erysipelas, furunculosis, chronic folliculitis and hydradenitis were selected for this disease group. BV was indicated according to the following criteria:

in the erysipelas group: who have had relapses at least 3 times a year;

in the folliculitis group: with routine dermatological therapy, new pustular formation has been regular for at least 3 months;

In the group of furunculosis: who have had multiple furuncles or a small number of furuncles that have recurred over time for at least 3 months (8);

in the hydradenitis group: who have had persistent inflammation of the apocrine glands for at least 3 months.

In each of the four chronic disease groups, patients with a past medical history of the previous year were burdened with diganosis, according to their cardboard. In these patients, BV was used as monotherapy to prevent relapses. In all cases, BV treatment was initiated at a stage when the patient was in remission due to the routine treatment we were applying. Patients were recalled three times during the 3-month intermittent treatment, always after a 10-day BV cycle, and a fourth time after another 3 months, during which time they had not taken BV anymore. Treatment was considered effective only if there was no recurrence in the observed period.

Our results are shown in Table 3 and in the graph (Table 3, Figure 1). It can be stated that the treatment time during acute events was significantly reduced with BV. Compared to an average healing time of 10.5 days in the control group, the average healing time for BV users is 6.75 days. This difference was highly significant (p <0.001) in the statistical analysis (Table 4). The rapid improvement in clinical symptoms, the short duration of nursing care and the consequent decrease in the number of days incapacitated for work justify our therapeutic aim (Figure 1).

It can be seen from the figure that the beneficial effect of BV capsule was demonstrated in all groups of diseases examined.

III. test

The efficacy of treatment of patients with atopic dermatitis was investigated in the following experiment:

We used BV therapy mainly in pediatric patients in a group of atopic dermatitis patients. The drug was administered in monotherapy, supplemented with only an inert topical ointment (Ung. Hydrophilicum nonionicum), and no soap or other detergent was used.

The drug was administered for 3 months, 10-10 days per month. After each 10-day course, patients were screened for control.

No side effects were observed during medication. BV was given during the winter months (December, January, February), when the skin condition of atopic patients is expected to worsen.

With the exception of one case, we found that all of our patients had fully reconstructed skin symptoms or significant improvement.

Complete asymptomatic 19 people 70% Significant improvement 7 people 26% Unchanged state 1 person 4%.

This clinical effect is considered excellent.

We believe that BV reduces circulating Ig Et in atopic dermatitis, presumably by restoring the subpopulation of T-secreting cells, inhibiting histamine secretion from disrupted mast cells, and most likely inhibiting autologous atopic dermatitis, a variant of allergic inflammation.

Based on currently known data describing the mechanism of action of the drug, the therapeutic use of BV in allergic dermatological disorders, especially where allergic inflammation, and in particular allergic autocytotoxicity, occurs.

HU 213 508 Β

We are currently successfully applying BV in addition to pyogenic and atopic dermatological disorders in a large group of allergic vasculitides such as:

- modular vasculitis,

- erythema nodosum,

- Mucha-Habormann disease, and

- in a wide range of superficial vasculitis accompanied by purpura.

These diseases account for almost half of current dermatological diseases.

Table 1

Brocho-Vaxom therapy for piodermal skin patients (1988)

Diagnosis Number of acute cases Chronic cases get sick. erysipelas 8 people 6 people folliculitis 13 people 8 people furunculus 46 people 11 people hydradenitis 6 people 3 people impetigo 15 people - Altogether: 88 people 28 people = 115 people

Table 2

Patients undergoing conventional treatment (1986) Diagnosis

Erysipelas 19 people

Folliculitis 22 fo

Furunculus 63 persons

Hydradenitis 6 people

Impetigo 102 people

Total: 212 people

Table 3

Evolution of recovery times

Group taking BV control Group Diagnosis Case / fo Average healing time Case / fo Average healing time erysipelas 8 9.13 ± 1.55 19 15.63 ± 4.9 folliculitis 13 9.23 ± 2.41 22 16 ± 5.76 furunculus 46 5.83 ± l, 70 63 8.63 ± 4.55 hydradenitis 6 8.83 ± 1.94 6 15.50 ± 6.48 impetigo 15 5.33 ± l, 40 102 9.21 ± 4.12 Altogether 88 X = 6.75 ± 1.78 212 X = 10.50 ± 4.12

Table 4

Computerized statistical analysis

SUN BY GY GROUP Sum of Mean Signif Source of DF F variation Squares Square of F Main Effects 2643.637 5 528.727 32.853 0.0 GY 996.971 1 996.971 61.948 0,000! GROUP 1771.335 4 442.834 27.516 0.0 Two-way Interact. 155.001 4 38.750 2,408 0.50 GY GROUP 155.001 4 38.750 2,408 0.50 Explalned 2798.638 9 310.960 19.322 0.0 Residual 4667.159 290 15.094 Global 7465.797 299 24.969

300 (212 + 88) Cases were processed.

Cases / 0.0 PCT / were missing.

According to the evaluation, there was a very significant statistically significant difference between the mean treatment time of BV patients and the control group (p <0.001).

Table 5

Broncho-Vaxom monotherapy in chronic relapsing cases

Diagnosis Number of cases successful ineffectual erysipelas 6 people 5 people 1 person folliculitis 8 people 6 people 2 people furunculus 11 people 9 people 2 people hydradenitis 3 people 3 people - Altogether: 28 people 23 people 5 people

Patent Claim Point

Claims (1)

A process for the preparation of a pharmaceutical composition comprising at least one of at least one bacterially acceptable bacterium of Haemophilus influenzae, Diplococcus pneumoniae, Klebsiella pneumoniae and ozaneae, Staphylococcus aureus, Streptococcus pyogenes, Streptococcus viridans and Neisseria catarrhalis. and transforming it into a pharmaceutical composition for treating atopic skin diseases.