JPH04211017A - Therapeutic drug for dermatitis - Google Patents

Abstract

PURPOSE: To obtain a medicine showing excellently treating effects on hypersensitive dermatitis, comprising a bacterium dissolved substance derived from a specific strain. CONSTITUTION: This medicine comprises a bacterium lysate which is derived from strains of Haemophilus influenzae serotype b (NCTC8467), Diplococcus pneumoniae serotype 1, 2, 3 and 47 (NCTC7465, 7466, 7978 and 10319), Klebsiella pneumoniae NCTC204 and 5056, Klebsiella ozaenae NCTC5050, Staphylococcus aureus I-049, I-050, I-051, I-052, I-053 and I-054, Streptococcus viridans I-046, I-047 and I-048, Streptococcus pyogenes group A (NCTC8191) and Branhamella catarrhalis I-045, NCTC3622 and 3625, concentrated and made lyophilic. The bacterium lysate is made into a form of a capsule for oral administration containing 7mg of the bacterium lysate.

Description

[Detailed description of the invention]

[00011

FIELD OF INDUSTRIAL APPLICATION The present invention relates to a drug for the treatment of hypersensitivity dermatitis, and more particularly to the new use of known bacterial lysates in the production of drugs for the treatment of the above-mentioned diseases. [0002] From Swiss patent CH 633,188 it is already known for an immunotherapeutic agent against respiratory tract infections containing as an active ingredient a bacterial lysate derived from at least one of the following strains of Staphylococcus aureus: l-049, l-050,
l-051, l-052, l-053 and l-054 - Streptococcus greenus l-046, l-047 and l-048 - S. catarrh l-045 and Haemophilus influenzae, serotype b NCTC8
467-Diplococcus pneumoniae, serotype 1. 2. 3 and 4
7NCTC7465, 7466, 7498 and 1031
9- Klebsiella pneumoniae NCTC204 and 50
56-Bacterium bronchus NCTC5050-Streptococcus pyogenes group A NCTC8191-Septococcus catarrh NCTC3622 and 3625NCTC
Strain C is from the National Collection of Type Cultures.
of Type Cultures) 175 Co11ndale Avenue, London NW95HT, Great Britain (175 Co11ndale Avenue)
, LondonNW95HT, GreatBri
tain) and is available to the public, while the ■ strain was published on March 14, 1978 by the owner of the above-mentioned patent in the National Collection of Microorganic Cultures, Pasteur Institut: y-- (Natio-nal Co11
Ection of Microorganism C
u1tures, Pa5teur In5titut
e) 28, Root Doctorow, F-75724
, Paris, France (28, rue due Dr Ro
ux, F-75724, Paris, France
) is registered. [0003]

Bacterial lysate protected by the above-mentioned Swiss patent shows, in a completely unexpected manner, a significant effect on hypersensitivity dermatitis, a chronic, genetically determined disease. Ta.

Recent studies have shown that hypersensitivity dermatitis is a complex complex characterized in particular by a weak response of cell-mediated delayed sensory hypersensitivity (weak skin response) and an increase in immunoglobulin E (IgE) synthesis. It was shown that it may be associated with immune deficiency. Furthermore, the gastrointestinal tract may act as a gateway for disease-causing allergens. [0005] The present invention therefore provides the use of bacterial lysate derived from at least one of the following strains for the manufacture of a medicament for the treatment of hypersensitivity dermatitis: Haemophilus 1nfl
uenzae), serotype b
NCTC8467 Diplococcus pneumoniae
iae), serotype 1. 2. 3 and 47 NCTC
7465, 7466, 7978 and 10319 Klebsiella pneumonia
e) NCTC204 and 5056 Klebsiella ozaenae
NCTC5050 Staphylococcus aureus (Sta
phylococcus aureus)
l-049, l-050, l-051゜l-052, l
-053 and l-054 Green Streptococcus
coccus viridans) l-0
46, l-047 and l-048 Streptococcus pyogenes (Str
Eptococcus pyogenes), group ANCTC8191 Branhamella catarrh
alis) (Previously Ne1sseria cataar
rhalis) I-045, NCTC3622 and 625. Preferably, the bacterial lysate is derived from all the above-mentioned bacterial strains and is provided in concentrated and lyophilized form. The medicament is preferably manufactured in the form of a capsule for oral administration. Each capsule contains 7 mg of lyophilized bacterial lysate. [0006] The following describes, by way of example, the preparation of bacterial lysates and galenic forms of drugs.
and the results of clinical trials. [0007] Preparation of Bacterial Lysates Basic sterile standard media can be prepared for all bacterial strains. It contains the following materials in the amounts indicated below for a final volume of 11. [0008] Sodium chloride 2.5 g Sodium phosphate-hydrogen 2 g Sodium acetate 0.5 g Aneurine 0.003 g Nicotinic acid 0.003 g Sodium lactate (70% lee) 2 ml Ammonium lactate (50% solution) 2 ml Meat Extract 22.
5 g Yeast Extract 7.5 g Glucose 3 g Different strains are cultured in liquid medium under optimal conditions. The basal medium is preferably enriched with yeast extract to 2% and Fildes extract to 0.5% for culturing H. influenzae strains. Also preferably, the basal medium is enriched with up to 0.5% horse serum and up to 0.3% glucose for culturing diplococcus pneumoniae. [0009] Finally, the same basal medium is preferably 0.3
% glucose for culturing other bacterial strains, namely Klebsiella pneumoniae and Klebsiella bronchialis, Staphylococcus aureus and Staphylococcus catarrhalis. (00101 These separate cultures were incubated at 37°C in a fermenter;
Grown at pH 7. After being harvested and counted, the bacteria are centrifuged and suspended in saline solution for each strain separately. Suspensions of various bacteria are then subjected to alkaline lysis under standardized conditions of pH (9-10) and temperature (20-40°C), and the opening process is observed using a microscope.

The volume of lysate coming from each bacterial strain is then adjusted by the number of bacteria and the final volume of concentrate. The various lysates are then mixed in appropriate proportions and centrifuged. The supernatant is diluted in saline solution to the final volume calculated for each production batch. The concentrate is then thoroughly filtered (i
n-depth filtration) and then sterilized on a 0.2μ membrane. The product is then tested chemically and microbiologically. It can be stored at 4°C. [0012] Preparation of Capsules Prior to preparing the selected galenic form, the bacterial lysate concentrate is neutralized in a known manner;
This concentrate is then made lyophilic to obtain a lyophilized product which is aseptically collected, filtered and stored under vacuum in a suitable container. The product thus obtained, called "standardized lysate", contains 40 mg versus 7 mg of preferably lyophilized bacterial lysate, which will constitute the active ingredient of future drugs. This standardized lyophilic substance is subjected to chemical and microbiological quality control. [00131 Pharmaceutical capsules for oral administration are then also prepared in a known manner. Each capsule contains 40 μ of standardized lyophilized material. For example, Capsuge
Capsules of type l) are filled with a mixture of lyophilic material and suitable excipients readily selected by those skilled in the art. [0014] Toxicity Studies Acute toxicity studies to determine the lethal dose 50 (L, D, 50) at doses up to 5.000 mg per body weight showed that the drug had no toxic effect. Furthermore, gross and microscopic examination did not reveal any changes in the animal's organs. [0015] Clinical Trial A clinical trial was conducted on the drug prepared as described above to determine its effect on hypersensitivity dermatitis. Twenty-six adult patients with long-standing hypersensitivity dermatitis were treated with the drug for 5 months. The drug was administered at a dosage of 1 capsule (7 mg of bacterial lysate) per day for 1 month and then for 10 days each in months 3, 4 and 5 of the study. One year earlier, 15 of these patients had already received the drug at the same dosage for five months. [0016] Special attention was paid to the discomfort of itching and dermatitis with "lichenification", which was evaluated monthly on the following criteria: 20 - none, ■ = some, 2 = moderate;
3 = Terrible, 4 = Very Terrible. [0017] Clinical improvement was considered when the severity of symptoms (itch and dermatitis) and use of usual treatments disappeared by more than 50%. Serum IgA, IgG and IgM levels (
(measured by radioimmunodiffusion) and total serum IgE levels (measured by radioimmunoassay) were determined before the study and after 1 and 5 months of treatment, respectively. [0018] Cell-mediated skin test (CMI multi-test)
It was done again. Clinical improvement was observed in 57.7% of the 26 patients treated during the 5 months of the study. If only the 15 patients treated for two 5-month periods were considered, improvement was seen in 73.3% of them. [0019 Serum IgA, I in 126 patients
gG, IgM and IgE levels showed a statistically significant decrease after 1 and 5 months of treatment (Table 1). [0020] In 15 patients treated with the drug for 12 periods, a statistically significant decrease in IgE levels was observed at the end of the first period and more pronounced during the second period. (Table 1I). (The 00211 skin test (CMI Multitest) showed a weak response (reflecting cellular immune deficiency) in 26 patients before treatment, i.e. 7.21 ± 1.5 mm, but it remained unchanged for 5 months after treatment. Later the normal level i.e. 22.25±2.7
mm (normal means a value of skin stiffness varying between 18 and 28 mm). [0022]

Effects of the Invention The results of the tests carried out in this way show that the drug according to the invention has a remarkable effect on hypersensitivity dermatitis. [0023]

[Table 1] Table 1 Average serum IgA in 26 patients with hypersensitivity dermatitis treated for a single 5-month period, 11! G
, kM and It! E level parameter initial level
After 1 month p = After 5 months p
=IgA(III/ml> 332.62±17.2
9 313.23±18,42 0,077 3[
16,15±16. ．． 36 0.012 IgG (Ill
/m) 1844.2 total 68.18 1687.31
±59,62 0.001 1672.69: Hi60,
72 D, 004Igllll (10/ml) 22
8.84±12.74 182.31± 8,22
0.0001 195.7a±11.86 [1,0
02IgE (Ill/ml> 1935.54dhi46
8,65 1553.08±368,49 0,007
1286.46 Nihi 281.311 0.012[0
024]
Table 2: Average serum 1 g in 15 patients with hypersensitivity dermatitis treated for two 5-month periods
B level average 1. E level (II/ml) Exam period Initial level 1 month later
5 months later 1st 4593.6±1 [189,643
15,4±1014. Ill" 3304.1±8
19.5” 2nd 2!1lfil, ?±[18L6
2329.7±530.9”” 1888.6±38
4.33”””p = 0. (138 ←p = 0.007 ”p = 0.008 Amount + Medium p = (1,014

Claims (4)

[Claims] 1. Use of a bacterial lysate derived from at least one of the following strains for the manufacture of a medicament for the treatment of hypersensitivity dermatitis: Haemophilus 1nfl
uenzae), serotype b
NCTC8467 Diplococcus pneumoniae
iae), serotype 1. 2. 3 and 47 NCTC
7465, 7466, 7978 and 10319 Klebsiella pneumonia
e) NCTC204 and 5056 Klebsiella ozaenae
NCTC5050 Staphylococcus aureus (Sta
phylococcus aureus)
l-049, l-050, l-051゜l-052, l
-053 and l-054 Green Streptococcus
coccus viridans) l-0
46, l-047 and l-048 Streptococcus pyogenes (Str
Eptococcus pyogenes), group ANCTC8191 Branhamella catarrh
alis) (Previously Ne1sseria cataar
rhalis) I-045, NCTC3622 and 625 2. Use according to claim 1, characterized in that the bacterial lysate is derived from all the bacterial strains mentioned in claim 1. 3. Use according to claim 1 or 2, characterized in that the bacterial lysate is in concentrated and lyophilized form. 4. Use according to any one of claims 1 to 3, characterized in that the medicament is provided in the form of capsules for oral administration, each capsule containing a daily dose of 7 cm of bacterial lysate. .