FR2658419A1 - MEDICAMENT FOR THE TREATMENT OF DERMATITIS. - Google Patents

Abstract

The present invention relates to the use of a bacterial lysate in concentrated and lyophilized form originating from one of the following strains: Haemophilus influenzae (serotype b), Diplococcus pneumoniae (serotypes 1,2,3,47), Klebsiella pneumoniae, Klebsiella ozaenae , Staphylococcus aureus, Streptococcus viridans, Streptococcus pyogenes (serogroup A), Branhamella catarrhalis (former Neisseria catarrhalis), for the manufacture of a medicament for the treatment of atopic dermatitis.

Description

1 - MEDICAMENT FOR TRA-r Mf Nil 'OF DERMATITIS The present invention

relates to medication for

  the treatment of atopic dermatitis, and more particularly

  lier to the new use of a known bacterial lysate, for the manufacture of a medicament intended for the

  treatment of the aforementioned disease.

  Already known from the Swiss patent CH 633 188, property of the same holder, an immunobiotherapeutic drug against infectious diseases of the respiratory tract,

  containing as active ingredient a bacterial lysate from

  from at least one of the following strains: Staphylococcus aureus 1-049, 1050, 1-051, 1-052,

1-053, I-054

  Streptococcus viridans 1-046, 1-047, I-048 Neisseria catarrhalis I-045 and at least one of the following strains: Hemophilus influenzae serotype b NCTC 8467 Diplococcus pneumoniae serotypes 1, 2, 3, and 47

NCTC 7465, 7466, 7978, 10319

  Klebsiella pneumoniae NCTC 204, 5056 Klebsiella ozaenae NCTC 5050 Streptococcus pyogenes group A NCTC 8191 Neisseria catarrhalis NCTC 3622, 3625%, 2 -

  NCTC strains are cataloged by the National Col-

  lection of Type Cultures, London, Colindale Avenue 175, London NW 9 5 HT (GB) and accessible to the public, while strains I were deposited by the aforementioned patent holder on March 14, 1978 with the National Collection of Cultures of microorganisms, Institut Pasteur, 28 Rue

from Dr Roux, 75724 Paris (FR).

  All these strains come from responsible germs

  infectious diseases of the respiratory tract.

  However, the bacterial lysate which is the subject of the aforementioned Swiss patent has demonstrated a remarkable effect, and this quite unexpectedly, on atopic dermatitis

  which is a chronic hereditary disease.

  Recent studies have shown that dermatitis ato-

  spike is linked to a complex immune deficiency,

  characterized in particular by weak hypersensitivity reactions

  delayed cell-mediated bility and increased synthesis of immunoglobulin E (Ig E) In addition, the gastrointestinal tract can serve as a gateway for

  allergens responsible for the disease.

  Consequently, the object of the present invention

  consists of the use of a bacterial lysate such as

  finished in claim 1 for the manufacture of a

  drug for the treatment of atopic dermatitis.

  Preferably, the bacterial lysate comes from all the strains mentioned in claim 1, and is

  present in a concentrated and freeze-dried form

  dicament is preferably produced in the form of cap-

  3 - sules for oral administration containing

  each 7 mg of lyophilized bacterial lysates.

  We will now describe, by way of example, the preparation

  tion of bacterial lysates, as well as a dosage form

  of the drug and the results of clinical tests.

  Preparation of bacterial lysates A standard sterile standard culture medium can

  be prepared for all strains; it contains the sub-

  following stanzas, in the quantities indicated for a

final volume of 1 lt.

  Sodium chloride Sodium monohydrogen phosphate Sodium acetate Aneurine Nicotinic acid Sodium lactate (70% solution) Ammonium lactate (50% solution) Meat extract Yeast extract Glucose 2.5 g 2 g 0.5 g 0.003 g 0.003 g 2 ml 2 ml 22.5 g 7.5 g 3 g The different strains are grown separately in

  optimized conditions, in liquid medium.

  The base culture medium is preferably enriched

  2% with yeast extract and 0.5% with ex-

  trait de Fildes, for the culture of the Hemophilus 4-influenza strain. Also preferably, the base medium is enriched to 0.5% with horse serum and to 0.3% with glucose

  for the culture of Diplococcus pneumoniae strains.

  Finally, the same basic medium is preferably enri-

  0.3% chi with glucose for the culture of the other strains respectively Steptococcus viridans and pyogens, Klebsiella ozaenae and pneumoniae, Staphylococcus aureus and

Branhamella catarrhalis.

  These separate cultures are grown in a fermenter,

370 C and a p H of 7.0.

  After harvesting and counting, the germs are centered

  run away and suspended in a saline solution, always

  separately for each of the strains.

  The various bacterial suspensions are then

  alkaline lysis under standard conditions

  p H (approx. 9-10> and temperature (approx. 20-40 'C)),

  the evolution being monitored under a microscope.

  Then, the volume of lysate from each bacterial strain is adjusted according to the number of germs and according to

  the final volume of concentrate The various lysates are

  then mixed in the appropriate proportions, then center

  The supernatant is diluted in a saline solution.

  to a final volume calculated for each production batch.

  The concentrate is then purified by deep filtration.

  finally sterilized on 0.2 μl membrane The product is then tested chemically and microbiologically It can be stored at 40 C. Preparation of the capsules

  Even before the preparation of the chosen dosage form

  sie, we proceed in a manner known per se to a neutralization

  tion of the bacterial lysate concentrate, then lyophi-

  Use of this concentrate to obtain a lyophilisate, which is aseptically harvested, sieved and stored under vacuum in a suitable container. The product obtained called standardized lyophilisate preferably contains, for 40

  mg, 7 mg lyophilized bacterial lysates, which

  will have the active ingredient of the future drug This lyophilisate

  standardized is finally subjected to a chi-

mique and microbiological.

  Then, capsules of the medicament for oral administration are also prepared in a manner known per se, each containing 40 mg of standardized lyophilisate, by filling capsules, for example of the Capsugel type,

  with a mixture of said lyophilisate and suitable excipients

  required easily chosen by the skilled person.

  Toxicity tests Acute toxicity studies in mice, with doses up to 5,000 mg / kg body weight to determine the lethal dose 50 (LD 5 O), have shown that the drug

  has no toxic effect Macro and microsco-

  moreover, no organ changes were revealed. -6Clinical tests

  In the clinic, tests were carried out with the

  cament thus prepared to study its effects on the derma-

  atopic tite 26 adult patients with long-term atopic dermatitis (AD) were treated with the drug for 5 months The drug was administered as one capsule (7 mg of bacterial lysate) per day, for 1 month, and for 10 consecutive days in each of the 3 rd, 4 th and 5 th months of the study 15 of these patients had already received the drug, at the same dosage, for 5

  also months but 1 year ago.

  Particular attention was given to the degree of

  severity of pruritus and dermatitis with "lichenifica-

  tion "which was assessed monthly using the following scale

  boasts: O = absent; 1 = light; 2 = moderate; 3 = severe and

4 = very severe.

  Clinical improvement was considered when the severity of symptoms (pruritus and dermatitis) and the use of

  conventional therapies have fallen by more than 50%.

  The serum level of immunoglobulins A, G and M (measured by radial immunodiffusion) and the overall serum level of Ig E (measured by radioimmunological techniques) were determined before the study, and after 1 and 5 months of

treatment respectively.

  Cell-mediated skin tests (Multitest CMI) were also used. Clinical improvement was observed in 57.7% of the 26 patients treated during the 5 months of the study If we consider the 15 patients who were treated during 2 periods of 5 months, we note

  improvement in 73.3% of cases.

  The immunoglobulin A, G, M and E levels in the 26 patients show a statistically significant drop

  after 1 and 5 months of treatment (see Table I).

  In the 15 patients treated with the drug

  in 2 periods, there is a statistically decrease

  significant of the Ig E level at the end of the first peri

  ode which is accentuated in the 2nd period (see Table II).

  Skin tests (Multitest CMI) showed in the 26 patients a weak response before treatment (reflecting a deficiency in cellular immunity), i.e. 7.21 + 1.5, which

  increases after 5 months of treatment to reach values

  their normal values, i.e. 22.25 + 2.7 mm (the normal average values of skin induration being between

about 18 and 28 mm).

  Thus, it appears from the results of the tests carried out

  that the medicament according to the invention exhibits a

  marked on atopic dermatitis.

-8-

Table I:

  Average level of immunoglobulins A, G, M and E in 26 patients with AD treated during a single period of 5 months. Parameter Values After 1 month p = After 5 months P = Initial Ig A (IU / ml) 332.62 + 17.29 313.23 + 18.42 0.077 306.15 + 16.36 0.012 Ig G (IU / ml) 1844.23 + 68.18 1687.31 59.62 0.001 1672.69 + 60.72 0.00 Ig M (IU / ml) 228.84 + 12.74 182.31 + 8.22 0.0001 195, 73 + 11.86 0.002 Ig E (IU / ml) 1935.54 + 468.65 1553.08 + 368.49 0.007 1286.46 281.38 0.01 Table II: Average Ig E level in the 15 patients with DA treated

during 2 periods of 5 months.

  Average Ig E values (IU / ml) Study period Initial values After 1 month After 5 months 1st 4,593.6 1,089.6 4,315.4 1,014.8 * 3,304.1 819.5 ** 2nd 2,961.7 + 681.6 2329.7 530.9 *** 1888.6 + 384.33 **** * p = 0.038 ** p = 0.007 *** p = 0.008 **** p = 0.014

Claims (4)

9 CLAIMS CLAIMS   1 Use of a bacterial lysate from at least one of the following strains: Haemophilus influenzae, serotype b NCTC 8467 Diplococcus pneumoniae, serotypes 1,2,3,47 NCTC 7465, 7466, 7978, 10319 Klebsiella pneumoniae NCTC 204, 5056 Klebsiella ozaenae NCTC 5050 Staphylococcus aureus 1-049, 1-050, 1-051, 1-052, 1-053, I-054 Streptococcus viridans 1046, 1-047, I-048 Streptococcus pyogenes, group A NCTC 8191 Branhamella catarrhalis 1- 045, NCTC 3622, 3625 (anc Neisseria catarrhalis) for the manufacture of a medicament intended for the treatment atopic dermatitis.   2 Use according to claim 1, characterized in that the bacterial lysate comes from all   strains mentioned in claim 1.   3 Use according to claim 1 or the claim   tion 2, characterized in that the bacterial lysate is   in concentrated and lyophilized form.   4 Use according to one of claims 1 to 3, ca-   characterized by the fact that the medicament is in the form of capsules for oral administration, each capsule containing as a daily dose 7 mg of bacterial lysate.