FR2528310A1 - TOPICAL PHARMACEUTICAL PREPARATIONS HAVING ANTISEPTIC ACTIVITY AND IMPROVED ANTIINFLAMMATORY ACTIVITY AND PROCESS FOR THE PREPARATION THEREOF - Google Patents

Abstract

THE PRESENT INVENTION RELATES TO NEW PHARMACEUTICAL COMPOSITIONS WITH ANTI-INFLAMMATORY ACTIVITY. THEY ARE CHARACTERIZED IN THAT THEY CONSIST OF 9A-FLUORO-11B, 21-DIHYDROXY-16A, 17A-ISOPROPYLIDENEDIOXYPREGNA-1,4-DIENE-3,20-DIONE AND DICHLORORHYDRATE OR 1,6-BULCIS5ATE - (4-CHLOROPHENYL) -BIGUANIDO-HEXANE MIXTURES IN A FIXED RATIO BETWEEN 1: 1 AND 1: 50 (IN PP) AS ACTIVE CONSTITUENTS. TOPICAL DRUGS WITH INCREASED ANTI-INFLAMMATORY ACTIVITY.

Description

The present invention relates to preparations for

  antiseptic, stable, topical pharmaceutical preparations,

  feeling increased double anti-inflammatory activity

  which are suitable for the treatment of primary infections

  mayors accompanied by topical inflammations, mainly dermatoses, and a process for their preparation.

  Ointments containing antibiotics (ie

  ie chloramphenicol, oxytetracycline, neomycin, gentamycin, etc.) or antiseptics

  (i.e. clioquinolum: 5-chloro-8-hydroxy-7-iodo

  quinoline, hexachlorophene: 2,2'-dihydroxy-3,3 ', 5,5',

  6,6'-hexachloro-diphenylmethane, etc.) as a constituent

  active killers, are widely used for the treatment of various skin infections However, these preparations

  exert an action only on the bacteria inducing the in-

  fection itself, but they fail to influence

  directly on the annex inflammation.

  For the treatment of inflammatory dermatoses, especially in chronic cases, it is often used

  anti-inflammatory ointments that contain corticosteroids

  steroids mainly, in addition to the antibacterial treatment.

  The use of compound combinations in the form of ointments containing both an antibacterial agent and a corticosteroid, that is to say: ("R" representing the trademark, the chemical name of the ingredient, is between parentheses), Chlorocid-HR (antibacterial component: chlorophenic, including corticosteroid: hydrocortisone),

  Tetran-Hydrocortison R (antibacterial component: oxyte-

  cyline, corticosteroid component: hydrocortisone), Predniso-

  lone JR (antibacterial component: 5-chloro-S-hydroxy-7-iodine

  quinoline, corticosteroid component: prednisolone), or

  antimycotic agent and corticosteroid, i.e.

  fucort R (including antimycotic: pimaricin, corticosteroid component: hydrocortisone), Micosolone R (component

  antimycotic: 1-Z, 4-dichloro (2,4-dichloro-benzyloxy) -

  phenethyl-imidazol, corticosteroid component: 21-deoxy21- (4-methyl-piperazino) -prednisolone hydrochloride) etc. for the treatment of inflammatory diseases and other cutaneous disorders, ie eczema, can be considered as being real progress, although even dual-target associations fail to resolve

  problems caused by the application of a single component.

  These problems can be summarized as follows: The antibacterial range of antibiotics used in these preparations is quite narrow Thus, the

  oxytetracyline component present in Tetran's ointment

  Hydrocortisone is, by far, insufficiently active against Gram-negative bacteria like Pseudomonas, Proteus and

  Klebsiella or Gram-positive bacteria such as Staphylo-

  coccusaureus or Streptococci, while the chloramphenicol component in Chlorocid-HR ointment is not sensitive enough to Pseudomonas and Gram-negative Proteus strains and Straphylococcus aureus strains.

Gram-positive Streptococcus.

  Moreover, when using all the pre-

  dermatological partes containing an antibiotic, it quickly develops resistance to antibiotics It follows that not only the treatment fails to provide the expected relief in the patient, but in addition, it can even promote the proliferation of bacteria

  resistant pathogens, too (Antibiotics and Chemo-

  rapy, Churchill Livingstone Ed, London, 1981, p 306).

  It can also be noted that these preparations constitute

  kill rather poor anti-mycotic agents and that their application may even induce the increased proliferation of

  dermatological mycotic population (Guidelines for the Pres-

  Pharmaceutical Preparations, Medicina Press, Budapest 1980, p 479) Thus, allergies are often detected

  after use of the preparations above.

  Although the antibacterial range of aminoglycoside antibiotic agents (i.e., neomycin, gentamycin) is relatively larger, they exhibit significantly higher toxicity than the first agents, which affects the kidneys and the kidney. hearing, even after topical administration

larger quantities.

  Of the antiseptic agents applied in the last

  matology, the use of 5-chloro-8-hydroxy-7-iodo-quinoline

  line (clioquinolum), a broad-spectrum preparation, is limited because it has the property of inducing irritation or skin allergy because of its iodine content, so it can not be used at all in Martindale iodine sensitive patients: Extra Pharmacopoeia, The Pharmaceutical Press, London, 1977, pp. 27, 72, and 823; JAMA 201, 1009 (1967); JAMA 202, 710 (1967); Arch Derm 106

  335 (1972) In addition, she stains clothing and lingerie.

  Side effects of antiseptic agents, most of

  part of them being rather toxic, are not neglected

  also, since they are absorbed through the skin.

  In recent years, it has been found that hexachlorophene can seriously affect the nervous system (Journal, 240, 513 (1978); J Clin Pathol 34, 25 (1981); Lancet 1982/1 87,

  There is another disadvantage in that antibiotics are

  ticks and other antibacterial agents, such as hexachloro-

  phene, iodine, mercury compounds, induce inflammation

  As a side effect, due to their allergenic activity, this danger becomes even clearer because of the inherent superior predisposition of eczematous patients.

  allergic inflammations (polysensitization).

  Ointments containing antimycotics are generally poor antibacterial agents, both

R R

  alone and in combination (Pimafucort, Mycosolon, etc.), so that their antibacterial range is narrower and they can be applied profitably only after examination

  confirming the presence of a mycotoxin infection.

if that.

  In dermatological ointments, the compounds

  Antiinflammatory drugs are mainly corticosteroids. When applied locally, they have an excellent therapeutic value, but at the same time they reduce the

  skin resistance to bacteria, fungi and viruses.

  As a result, they induce secondary infections that manifest themselves by a development of purulence and pustules, when applied to an inflamed skin surface. Moreover, because of their high corticosteroids, they can cause side effects.

  systemic features that are characteristic of the steroids of

thesis.

  The dermatological associations listed below

  can not be considered as being developed or ideal from the practical point of view, since their use is only recommended following the previous identification of the pathogenic organism As the dermatological treatment is continued in treated patients at home, a culture is rarely performed, so that the consequence of the treatment can never be

  predicted All listed preparations may

  cause localized hypersensitivity, itching, hives, skin irritation, skin burn, and maculopapular rash (Chlorocid-H R) (Guidelines for Drug Prescription, Medicina

Press, Budapest, 1980, p 128).

  The object of the present invention is to develop a topical antiseptic and anti-inflammatory pharmaceutical preparation free from the disadvantages presented by the above combinations, which is stable and can be

  applied also in cases where the preparations set out

  do not succeed in provoking the cure of the patient.

  It has been found that the antiseptic and anti-inflammatory effect of topical pharmaceutical preparations

  containing 0.025 to 0.25% (w / w) 9-fluoro-l, 21-

  dihydroxy-16α, 17α-isopropyl-idenedioxy-pregna-1,4-diene-

  3.20-dione (triamcinolonacetonide) and from 0.25 to 2.5% (w / w)

  of 1,6-bis-1-5-chlorophen dihydrochloride or digluconate

  nyl) -biguanido-hexan (dihydrochloride or chlorohexidine digluconate respectively), is significantly higher than

  that provided by the known combinations and that these

  ci can be successfully applied for the treatment of primary and secondary dermatitis with inflammation, such as eczema nummulare, microbial, mycoticum cruris, impetiginosum, dyshidrosis, intertrigo, pemphigus vulgaris and superinfections like dermatitis of

contact.

  The subject of the present invention is therefore stable topical pharmaceutical preparations having

  antiseptic properties and anti-inflammatory properties

  In accordance with their preparation process,

  9α-fluoro-11,21-dihydroxy-16α, 17α-isopropylidenedioxy-

  Pregna-1,4-diene-3,20-dione and the dihydrochloride or diglycidyl

  1,6-bis- (4-chlorophenyl) -biguanido] -hexane conate are mixed in a fixed ratio between 1: 1 and 1:50 in w / w, and

  with the help of supports and / or vehicles generally applied-

  in pharmaceutical formulations, are converted

  according to methods generally used in the manufacture of

  medications, topical pharmaceutical preparations such as ointments, syrups, vaginal

  formulations containing 0.05 to 0.25% (w / w) of 9

  11,21-dihydroxy-16α, 17α-isopropylidenedioxy-pregna-1,4-

  diene-3,20-dione and 0.25 to 2.5% (w / w) dihydrochloride

  or 1,6-bisl-5- (4-chlorophenyl) -biguanido digluconate 7-

hexane as active ingredients.

  The active constituents of pharmaceutical combinations

  in accordance with the present invention, are compounds

  chlorohexidine dihydrochloride or digluconate

  can not be prepared according to a process described in the patent

  No. 175 371 and triamcinolon-acetonide by a procedure

  described in the Hungarian patent N 163 145.

  By combining the respective chlorohexidine salt

  and triamcinolon-acetonide according to the concentrations

  above, a new pharmaceutical composition is produced

  topical, which is more active than the compositions of the prior art.

  In view of the wide antibacterial range of the preparations, no resistance is induced during the treatment. As for the possible side effects of the industrial preparations with similar indications, these are appreciably attenuated. by the use of the composition according to the

present invention.

  The combination of triamcinolon-acetonide and the respective chlorohexidine salt according to the present invention,

  result in a combination that unexpectedly allows

  clinical trials, the successful dermatological treatment of patients who either do not respond to previous conventional treatments or

  unsatisfactory response By reducing the bacterial population

  the surface of the skin and more, exerting an effect

  secondary anti-inflammatory agent, chlorohexidine inhibits

  development of bacterial infections as well as inflammatory

  chronic skin disease, thus ensuring more

  advantageous for triamcinolon to exert its anti-

  inflammatory on the eczematous surface of the skin.

  The effectiveness of the combined preparation complies

  the present invention is demonstrated with a

  0.1% triamcinolon-acetonide and 1% dihydrochloride

  chlorohexidine, separated according to Examples 1 and 3 below.

1) Clinical trial

1.1 Preliminary, open study.

  Number of patients: 17 Diagnosis: dyshidrosiform eczema (11 cases),

pemphigus vulgaris (6 cases).

  Patients have not responded to conventional treatment Evaluation: there is no refractory case, the response is rapid, apparent and progresses to a state of patients completely devoid of symptoms No effect

secondary is not detected.

  1.2 Double-blind clinical trial.

  The reference substance used as a control

  contains only triamcinolon-acetonide (0.1% w / w).

  The two ointments, the association containing the dichlo-

  chlorohexidine hydrochloride and triamcinolon-acetonide

  and the preparation containing only triamcinolon-

  acetonide, are prepared with identical ointment bases and provided with a code number, so that neither the doctor nor the patient know which of the preparations is used The code number is not clarified until the end of The study The preparations are used for the treatment of skin infections appearing symmetrically on the body

  randomly chooses the side treated by each

  tion. Number of patients: 30 Diagnosis: eczema nummulare (19 cases) eczema mycoticum (3 cases), eczema impetiginosum (3 cases),

dyshidrosis (5 cases).

  The test data are established by the segmental method The results obtained with the combination are greater than those provided by the products.

industrial, p = 0.05.

  No side effects are observed.

  Evaluation: During the open study and the study in

  double-blind, it is confirmed that the ointment con-

  chlorohexidine dihydrochloride +

  triamcinolon-acetonide, has therapeutic

  extremely advantageous, even in dermatoses on which the previous conventional treatment completely failed No side effects and no allergies are observed in any of the cases According to the results obtained by the Applicant, the combination can cover the indication zones following: all eczema in which

  mycotic or bacterial factors are important

  primary or secondary education, such as eczémasnumular,

  microbial, mycoticum, cruris impetiginosum, dys-

  hidrosis, intertrigo, pemphigus vulgaris The ointment

  comprising the combination according to the present invention

  more recent developments in this field and more advantageous than preparations with similar indications, such as Prednisolone J,

R R R

  Tetran-Hydrocortisone, Chlorocid-H, Myocosolone

2) Open clinical trial.

  The ointment comprising the combination according to the

  The present invention is subject to a dermatological clinical trial.

logic on 71 patients.

  Distribution of patients according to the diagnosis: bacterial eczema 18 eczema mycoticum 13 eczema contactum 6 eczema endogenous 1 eczema ronicosum 2 balanoposthitis candida 3 ulcus cruris 3 acne pustulosa 7 dyshydrosis mani 7 dyshydrosis pedis 8 dermatitis intertriginosa 1

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  The culture of microscopic tests is carried out in 20 of the 71 cases and the following pathogenic bacteria

  are detected: Staphylococcus aureus, Klebsiella, Pseudo-

  monas aeruginosa, Proteus mirabilis, Escherichia coli, Candida

  albicans, Epidermophyta fungi The patients were previously treated with known preparations, which did not

  no healing in 53 (74.6%) of the 71 patients.

  The results of treatment with prepa-

  rations, applied before the ointment containing

  the combination according to the present invention, are assembled

in Table I:

TABLE I

  Previous therapy with industrial products. Applied product Efficiency Number of cases Ointments: Ung borosal *, Ung antisepticum, Ung jet, Ung Diachylon salic ,;

Ung Alum acet tart (Pharma-

  fungocort, Tetran-Hydrocortisone R, Fenofil gel Solutions: No effect 31 (55.35%) Sol Castellani, Sol tricolorm,

Fungifene R solution.

  Other formulations: Prednisolone R tablets, Trypsin R, Oxycort powder R spray Ointments:

R R

Lorinden R, Lorinden AR, Myco-

solone R, + Pimafucin R, Ung anti-

  septicum, ung salic 10% weak effect or 8 (14.28%) Other formulations: or R average Sol Castellani, Tetran talc Formulae Normal (Fo-No, V Hungarica, Medicina Press, Budapest, 1967) Fenistil (dimethindenum maleinicum) Ftorocort (triamcinolon-acetonide) Fungifene (pentachlorophenol) Mycosolone (mazipredonum hydrochloricum and miconazolum) Oxycort (oxytetracycline and hydrocortisone) Pimafucin (pimaricin) Trypsin (trypsinum and procaine hydrochloricum) Lorinden (flumethazolum pivalicum) Lorinden A (f lumethazolum pivalicum + acid, salicylicumn) Canesten (chlorotrimazol) Flucinar-N (fluocinolum acetonidum + neomycinum) TABLE 1 (continued) Ointments: u

Ung Diachylon Salic, Ung.

Alum acet tart (Pharmacopoea

Hungarica VI), Canesten R, Ftoro-

  cort R, Lorinden AR, Chlorocid-HR Solutions: Average Effect 11 (3.57%) Sol Castellani *, Spir Salic,

Tricolor sol, Fungifen R solu-

  Flucinar Ointment-NR Aggravation 2 (3.57%) Ointment Ung Borosalic Unsatisfied (1,7) By treating these same patients (71) with the ointment containing the combination according to the present invention,

  obtain a satisfactory result as a result of such treatment.

  in a major part (95%) of patients.

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  Evaluation of the treatment carried out with the ointment containing the combination of compounds according to the present invention,

  by determining the changes induced in five main

symptoms.

  Symptoms (oozing, crusts, hyperemia,

  pain, itching), are assessed by typical

  risking their gravity: 1 = no symtom, 2 = weak, 3 = medium, 4 = severe symptom Control studies are carried out

  before, during and after treatment.

  Percentage incidences of changes in symptoms observed before, during and after treatment are summarized in Table II using indices

characterizing their severity.

w w.L w CD i o

TABLE II

  a therapy with the ointment containing the combination according to the present invention

I A

  SYMPTOMS PERIOD OF OBSERVATION DISTRIBUTION OF SYMPTOMS IN%

  Severe (4) average (3) low (2) no symptoms (1) CROUTES Before treatment 23.7 51.5 22.2 2.6 Control I 4.6 45.8 39.7 9.9 At the end of treatment 2.9 1.5 4.4 91.2 SUINTE Before treatment 38.2 39.7 19.2 2.9 MENT Control I 7.6 47.9 29.8 14.7 At the end of treatment 1, 5 1.5 11.8 85, 2 HYPEREMIA Before treatment 38.4 51.4 7.3 2.9 Control I 14.7 54.1 28.2 3.0 At the end of treatment 2.9 4.4 17.6 75.1 PAIN Before treatment 19, 5 32.3 20.3 27.9 Control I 5.2 34.4 28.2 32.2 At the end of treatment 4.4 1.5 94.1 DEMAN Before treatment 29.5 38.2 29.4 2.9 GEAISON Control I 14, 3 32.1 28.2 25.4 At the end of treatment 1.4 2.9 3.4 92.3 N Ln mo LAI Table II shows that at the end of treatment,

  the five representative symptoms (crusts, oozing, hypere-

  pain, itching) are totally reduced, even eliminated in a major portion (95.3%) of patients (95.3% = average number of cases with a weak form)

  representative symptoms + cases devoid of symptoms).

  Side effects are only detected in 3 patients: low skin dryness in 2 patients and

pustules in a patient.

  The effectiveness of the ointment containing the combination

  according to the present invention is confirmed by the fact that whereas only 25.4% of the patients react to the conventional prior therapy, about 95% of the same patients show a positive response to the therapy performed with

  the preparation according to the present invention.

  The pharmaceutical ointment containing the combination may be prepared according to the method of this invention.

  invention, by mixing 9α-fluoro-11,21-dihydroxy-16α, 17α-

  isopropylidenedioxy-pregna-1,4-diene-3,20-dione and dichlo-

  Hydrochloride or 1,6-bis (4-chlorophenyl) digluconate

  biguanido 7-hexane in a ratio of 1: 1 to 1:50, with an oil-in-water emulsion as an ointment base, using vehicles and / or carriers used

  generally in the manufacture of medicine.

  A pharmaceutical ointment containing both the

  9α-fluoro-11β, 21-dihydroxy-16α, 17α-isopropylidene-dioxyprégna-

  1,4-diene-3,20-dione and 1,6-bis (4-chlorohydrochloride) dihydrochloride

  phenyl) -biguanidol-hexane can be advantageously prepared

  according to the process of the present invention, by homogenous

  neization of 0.05 to 0.25%, preferably 0.0 to 0.15% (calculated on the weight of the finished ointment), micromized powder

  9α-fluoro-11,21-dihydroxy-16α, 17α-isopropylidene-dioxygen

  Pregna-1,4-diene-3,20-dione with 0.5 to 2.0% of 1,6-bis-5- (4-chlorophenyl) -biguanido) -hexane dihydrochloride (230 mesh) and progressive addition to this mixture of active constituents, with constant stirring, the oil-in-water emulsion prepared elsewhere from the ointment base and homogenization

of the whole mixture.

  An oil-in-water emulsion as an ointment base may be advantageously prepared by heating up to about 10% paraffin oil (based on the weight of the finished ointment) having a viscosity of at least m Pa and 25% cetomacrogol, an emulsifying wax (B P. 1973, p 91) until the mixture is melted, and then the molten mixture is introduced into 60 to 65% of water, preferably having a temperature of 60 C L agitation is continued until

  cooling of the ointment base to room temperature

  The cold ointment base is homogenised with approx.

  1% of a solution containing a preservative

  Based on the weight of the finished ointment) Various benzoic acid derivatives, such as methyl or propyl p-hydroxybenzoate, may be preferably used.

as preservatives.

  A pharmaceutical ointment containing both

  9α-fluoro-11,21-dihydroxy-16α, 17α-isopropylidene-dioxygen

  Pregna-1,4-diene-3,20-dione and 1,6-bis / 5- digluconate

  (4-chlorophenyl) -biguanidol-hexane can be prepared according to

  according to the present invention, by adding 1,6-bis- (4-chlorophenyl) -biguanido-7-hexane digluconate in the form of a preferably 20% commercial solution, to the amount of water required. at the manufacture of the ointment, at approximately 60 ° C., then adding to the aqueous solution with constant stirring, the prepared oily melt

  according to the above method This ointment base is cooled

  die, first homogenized with a preservative, then

  with the required amount of 9-fluoro-11,21-dihydroxy-

  16α, 17α-Isopropylidenedioxy-pregna-1,4-diene-3,20-dione

  micronized, so as to provide a uniform homogenized ointment

* form. In addition to the foregoing, the invention also includes other arrangements which will be apparent from

the following description.

  The invention will be better understood by means of the

  description which will follow, which refers to examples

  plies of implementation of the method object of the present invention. It should be understood, however, that these examples of implementation are given solely for the purpose of

  illustration of the subject of the invention, of which they do not constitute

  in no way kill a limitation.

Example 1

  Preparation of a pharmaceutical ointment.

  1,6-Bis-5- (4-chlorophenyl) dihydrochloride 1.0 g biguanidol-hexane 9 e-Fluoro-16, 21-dihydroxy-16α, 17α-isopropyl 0.1 g lidenedioxy-pregna-1 , 4-diene-3,20-dione Paraffin oil (viscosity of at least 100 m Pa) 10.0 g Cetomacrogol emulsifying wax (BP 1973), 25.0 gp 91 Preservative solution (Pharmacopoea 1.0 g Hungarica VI, P 1314) Distilled water 62.9 g Cetomacrogol composition, emulsifying wax: cetylstearyl alcohol 20.0 g polyethylene glycol-1000 mono-cetyl ether 5.0 g Composition of the preserving solution: propyl paraoxybenzoate 30.0 g paraoxybenzoate of methyl 70.0 g spiritus concentratissinus 900.0 g

  The ointment can be prepared from

  above, in accordance with the following procedure: 10 g of paraffin oil and 25 g of ceromacrogol, emulsifying wax, are heated to 60 ° C on a water bath of water and the resulting melt is slowly poured

  under constant agitation, in 62.9 g of preheated water

  Also stirring is continued until cooling of the oil-in-water emulsion as an ointment base at room temperature. 1 g of the solution containing the preservative is homogenized with this ointment base. cold, the mixture is allowed to stand for 24 hours and is then milled on three cylinders.

  The mixture is stirred repeatedly and 1 g of dichlorohydrin are

  1,6-bis-5- (4-chlorophenyl) -biguanidol-hexane drate until it has a particle size of 230 mesh (0.069 mm) and then carefully mixed with it, 0.1 g

  9α-fluoro-11,21-dihydroxy-16α, 17α-isopropylidenedioxy-

  Micronized pregna-1,4-diene-3,20-dione and finally, this mixture is gradually combined with the ointment base prepared above,

  then the whole mixture is homogenized to form a pump.

made uniform.

Example 2

  Preparation of a pharmaceutical ointment:

  1,6-Bis / 5 (4-chlorophenyl) dihydrochloride

biguanido 7-hexane

  9? -Fluoro-1?, 21-dihydroxy-16?, 17? -Isopropyl?

  denedioxy-pregna-1,4-diene-3,20 dione Paraffin oil (viscosity of at least 100 m Pa) 1 Cetomacrogol, emulsifying wax (BP 1973, p 91) 2 Preservative solution (Pharmacopoea Hungarica VI, p 1314 ) Distilled water 6 2.0 g 0.05 g 0.0 g, 0 g 1.0 g 1.95 a The ointment is prepared from the components

  above, according to the procedure of Example 1.

Example 3

  Preparation of a pharmaceutical ointment:

  1,6-Bis (4-chlorophenyl) -biguanido dihydrochloride

  hexane 1.50 g 9α-Fluoro-11,21-dihydroxy-16α, 17α-isopropylidenedioxy-pregna-1,4-dienedione 0.15 g Paraffin oil (viscosity of at least 10.0 gm Pa) Cetomacrogol, emulsifying wax (BP 1973, 25.0 gp 91) Preservation solution (Pharmacopoea 1.0 g Hungarica VI, p 1314) Distilled water 62.35 g The ointment is prepared from the components,

according to the procedure of Example 1.

Example 4

  Preparation of a pharmaceutical ointment: 1,6-Bis / - (4chlorophenyl) dihydrochloride, 0.50 g biguanidol-hexane 9a-Fluoro-11e, 21-dihydroxy-16a, 17a-isopropyl 0.20g lidenedioxy -Pregna-1,4-dienedione Paraffin oil (viscosity of at least m Pa) 10.0 g Cetomacrogol, emulsifying wax 25.0 g (BP 1973) p 91 Preservative solution (Pharmacopoea 1.0 g Hungarica VI, p 1314) Distilled water 63.3 g The ointment is prepared from the components,

according to the procedure of Example 1.

Example 5

  Preparation of a pharmaceutical ointment:

  1,6-Bisl-5- (4-chlorophenyl) -biguanido digluconate 7-

  hexane in a 20% aqueous solution 5 9? -Fluoro-115,21-dihydroxy-16?, 17? -isopropyl? -dioxypregna-1,4-diene-3,20-dione Paraffin oil ( viscosity of at least 100 m Pa) Cetomacrogol, emulsifying wax (BP 1973, 25 p 91) Preservation solution (Pharmacopoea Hungarica 1 VI, p 1314) ml 1 g 0 g 0 g 0 g Distilled water 58.9 g The ointment is prepared from the above components according to the procedure described below: 5 ml of chlorohexidine digluconate solution are added to 58.90 ml of distilled water heated to 60 ° C. The combined components of the lipoid phase 10 g of liquid paraffin and 25 g of cetomacrogol, emulsifying wax, are also heated at 60 ° C. on a water bath of water and poured slowly, with constant stirring in the aqueous solution.

  containing chlorohexidine digluconate.

  Stirring is continued until cooling

  mixture at room temperature, then 1 g of the preservation solution is homogenized with this ointment and the whole mixture is added gradually to the above amount of triamcinolon-acetonide, and then homogenized to a uniform ointment This is left standing for 24 hours and then

  sent through a three-cylinder mill.

  As is apparent from the foregoing, the invention

  tion is not limited to those of its modes of implementation, of realization and of application which have just been described more explicitly; on the contrary, it embraces all the variants that may come to the mind of the technician in the field, without departing from the scope or scope of the

present invention.

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Z 528310

Claims (4)

  Stable topical pharmaceutical preparations having increased antiseptic properties and anti-inflammatory properties, characterized in that they comprise 9-fluoro-11,21-dihydroxy-16α, 17α-isopropylidenedioxy-pregna-1 , 4-diene-3,20-dione and dihydrochloride   or 1,6-bis-5- (4-chlorophenyl) -biguanidol digluconate   hexane mixed in a ratio of between 1: 1 and 1:50 (in   p / p) as active constituents.   2 Process for the preparation of pharmaceutical preparations   stable topical products with anti-   increased levels of septic and anti-inflammatory   cation 1, characterized in that 9α-fluoro-11S, 21-dihydroxy-   16-ae, 17α-isopropylidenedioxy-pregna-1,4-diene-3,20-dione and   1,6-bis Z- (4-chloro) dihydrochloride or digluconate   phenyl) -biguanidol-hexane are mixed in a fixed ratio between 1: 1 and 1:50 (w / w) and are made, together with carriers and / or carriers generally applied in pharmaceutical formulations, in the form of preparations. topical pharmaceuticals such as ointments, syrups, vaginal ova or other formulations, containing 0.05 to   0.25% (w / w) of 9α-fluoro-11e, 21-dihydroxy-16α, 17α-isopropyl   pylidenedioxy-pregna-1,4-diene-3,20-dione and 0.25 to 2.5%   (in w / w) of 1,6-bis / 3- (4- (4-   chlorophenyl) -biguanidyl-hexane, as active components, using methods generally used in the manufacture of drugs.   Process according to Claim 2, characterized   in that 9α-fluoro-11S, 21-dihydroxy-16α, 17α-isopropylimide   denedioxy-pregna-1,4-diene-3,20-dione and the dihydrochloride   or 1,6-bisl-5- (4-chlorophenyl) -biguanidol digluconate   hexane are mixed, with application of vehicles and / or   supports generally used in the manufacture of   pharmaceutical mades, with an emulsion of the oil-in-water type s Evident ointment base.   4. Process according to claim 2 or 3, characterized   in that during the preparation of the ointment,   9α-fluoro-11β, 21-dihydroxy-16α, 17α-isopropylidenedioxy-   Pregna-1,4-diene-3,20-dione is applied as a micronized powder. Process according to claim 2 or 3, characterized in that during the preparation of the ointment the   1,6-bis-5- (4-chlorophenyl) -biguanido dihydrochloride 7-   -hexane is used in powder form with a particle size of 230 mesh (0.069 mm) and 1,6-bis <- (4chlorophenyl) -biguanidol-hexane digluconate in the form of an aqueous solution.