WO1984004675A1 - Capsules vaginales - Google Patents

Capsules vaginales Download PDF

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Publication number
WO1984004675A1
WO1984004675A1 PCT/DK1984/000042 DK8400042W WO8404675A1 WO 1984004675 A1 WO1984004675 A1 WO 1984004675A1 DK 8400042 W DK8400042 W DK 8400042W WO 8404675 A1 WO8404675 A1 WO 8404675A1
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WIPO (PCT)
Prior art keywords
capsule
starch
viscosity
oil
capsule according
Prior art date
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PCT/DK1984/000042
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English (en)
Inventor
Ann Marie Doucette
Henrik Boisen
Original Assignee
Hansens Chr Bio Systems As
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Publication date
Application filed by Hansens Chr Bio Systems As filed Critical Hansens Chr Bio Systems As
Publication of WO1984004675A1 publication Critical patent/WO1984004675A1/fr
Priority to DK35685A priority Critical patent/DK35685A/da

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66Microorganisms or materials therefrom
    • A61K35/74Bacteria
    • A61K35/741Probiotics
    • A61K35/744Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66Microorganisms or materials therefrom
    • A61K35/74Bacteria
    • A61K35/741Probiotics
    • A61K35/744Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747Lactobacilli, e.g. L. acidophilus or L. brevis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0034Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4858Organic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4866Organic macromolecular compounds

Definitions

  • the present invention relates to a method and a capsule for control ⁇ ling vulvo-vaginal infections .
  • antibiotic treatment has proved to be disadvantageous as antibiotics tend to kill the desi red microflora in the vagina as well, whereby the natu ral healthy microbial balance of the vagina is disturbed . This in turn often results in the condition becoming re-occurring as the pathogenic microorganisms often re-in ⁇ vade the vaginal environment without other microorganisms to check their growth .
  • a more preferred way of controlling vulvo-vaginal infections is to employ lactic acid bacteria so as to simulate the normal vaginal envi- ronment.
  • infections occu r when the pH of the vagina is too high such as at menstruation, or when the hor ⁇ monal balance is disturbed because of pregnancy or when taking oral contraceptives, thus promoting the growth of potentially pathogenic microorganisms such as Candida albicans, Trichomon ⁇ s vaginalis, Staphyfococcus aureus, Gardnerella, - Streptococci and various anaer ⁇ obic microorganisms which, conversely, were not assumed to th rive under the normal, slightly acidic conditions in the vagina .
  • pathogenic microorganisms such as Candida albicans, Trichomon ⁇ s vaginalis, Staphyfococcus aureus, Gardnerella, - Streptococci and various anaer ⁇ obic microorganisms which, conversely, were
  • lactic acid bacteria In the known use of lactic acid bacteria, either a fermented milk product containing Lactobaciili is introduced manually, or a slurry of dried Lactobacillus acidophilus (e.g . the product known as Floranorm, marketed by Danapharm) is introduced by means of a suitable applica ⁇ tor such as a disposable syringe.
  • a suitable applica ⁇ tor such as a disposable syringe.
  • the non-encapsuled products suffer from the disadvantage that their application is uneven, i . e. the distribution of the lactic acid bacteria in the vagina is not homogeneous .
  • the application me- thod may also be found to be inconvenient.
  • the products are rather fluid, they tend to run out of the vagina so that they do not have the desired effect.
  • a disadvantage of the product known from US Patent No. 3.639.566 is that the bacteria incorporated in the capsules are likely to have a limited stability, due to the content of moisture absorbed by the starch incorporated in the capsule so that the capsules may only be stored for limited periods of time. Further ⁇ more, when applied in the vagina, the capsule wilt take up moisture for which reason the capsule content tends to get lumpy; this may result in an uneven distribution over the vaginal area and probably a reduced effect.
  • the present invention provides capsules which are superior with respect to efficient introduction and distribution of an effective a- mount of lactic acid bacteria into the vagina, and correspondingly provides an efficient method for controlling vulvo-vaginal infections .
  • the capsules of the invention are improved over the known art by containing stabilized cells of lactic acid bacteria, which means that they may be stored at room temperature for several months while maintaining a high percentage of viability.
  • one aspect of the invention relates to a soluble capsule for controlling vulvo-vaginal infections which contains a stable, dried, viable concentrate of lactic acid bacteria dispersed in a pharmaceuti ⁇ cally acceptable fluid carrier.
  • the term “dried” indicates that the concen ⁇ trate has a water activity (a ) of not more than 0.2, calculated w according to the formula described by e. g . D . Demeyer, Fleischwirt- schaft 59(7) , 1979, p. 940.
  • the capsule is preferably a gelatin capsule, in particular a soft gelatin capsule.
  • the capsule may, however, also be a hard, but soluble gelatin capsule.
  • the capsule may be of any suitable shape such as a spherical or oblong shape, but for easy application it is preferred that the capsule be oval or egg-shaped .
  • the volume of the capsule is in the range of about 0.2-5.0, preferably about 1 .2 ml .
  • the capsule volume is in fact rather critical as the physical proper ⁇ ties of the paste vide below) set limits to the amount of paste mate ⁇ rial and thus the amount of bacteria per capsule which may adhere or be adsorbed to the vaginal mucosa without causing any significant discharge problems .
  • the capsules preferred for use according to the invention are those produced substantially according to the disclosu re of US Patents Nos . 1 ,970,396, 2, 152, 101 , 2,234,479 and 2, 288,327.
  • the count of viable lactic acid bacteria is at least 1 x 10 s , preferably at least 1 10 7 , more - preferably at least 1 x 10 s and most preferably in the range between about 1 10 9 and 1 10 11 , such as about 1 x 10 9 and 1 10 l ⁇ per capsule.
  • the dried, stabilized bacterial concentrate when incorporated in the capsules of the invention, is not totally moisture-free, but contains some internal moisture. I n order to obtain a stable, dried concentrate with such a high cell count of viable bacteria, it is, however, desi ⁇ rable that the water activity of the concentrate is in the range of 0.00-0.2, preferably in the range of 0.00-0.1 .
  • a suitable instrument for determining water activity is available from Novasima AG, Zurich, Switzerland .
  • the concentrate is mixed with a fluid car- rier.
  • a fluid car- rier it has been found that particular types of fluid carrier are extremely well suited both for an even distribution in the vagina and for maintaining a high stability (i . e. long-term viability) of the concentrate.
  • the carrier is thus primarily so selected that it will protect the freeze-dried bacterial culture from physical and/or chemical reactions which have a negative effect on cell stability (expressed as a loss of viability) . It has been found that the most important single factor for maintaining the stability of the concentrate is the low water activity of the culture/carrier mixture for the reasons stated above.
  • the carrier should also have a water activity in the range of 0.00-0.2, preferably 0.00-0.1 .
  • the carrier is preferably a non-hygroscopic carrier to substantially prevent water uptake th rough the capsule wall which would decrease bacterial stability.
  • the fluid carrier should also be one which secures a homogeneous distribution of the bacteria in the vagina and an optimal contact with the vaginal mucosa upon the release of the carrier from the partly- dissolved capsule but which, on the other hand, does not cause the carrier material to run from the vagina immediately after application .
  • a carrier containing a bacterial concentrate has a certain thixotropicity, i . e.
  • the viscosity of the carrier within the capsule is sufficiently high to ensu re that there is little movement of the carrier during handling or transportation of the capsules, thereby avoiding any movement of the dried concentrate which might increase the exposu re of the concentrate to the inner capsule wall and thus increase the possibility that the cultu re might receive moistu re from the su rroundings .
  • This emphasis on a certain viscosity of the fluid carrier distinguishes the capsule of the inven ⁇ tion from capsules intended for oral administration , which contain lactic acid bacteria in a fluid carrier (e. g .
  • LactofloraTM marketed by Camette ApS, Esbjerg, Denmark
  • the fluid carrier in the known capsules does not have a sufficient viscosity to prevent sedimentation of the bacteria and possible uptake of moisture so that cell stability is likely to be impai red .
  • the capsule of the invention should contain a fluid car ⁇ rier with a viscosity of at least 2000 cps at a temperatu re of 20°C, as this viscosity is sufficient to secu re a satisfactory cell stability, while not being too high to prevent a "melting down" in the vagina to ob- tain a sufficiently low viscosity at the vaginal temperature for the above-mentioned homogeneous distribution to take place.
  • the carrier has a viscosity of at least 3000 cps, in particular at least 4000 cps at 20°C, it will still have a behaviou r with respect to consistency which is very well suited for effective distribu ⁇ tion of the bacterial culture under the conditions prevailing in the vagina .
  • a capsule containing such a carrier with a concentrate of lactic acid bacteria may suitably be administered when the patient goes to bed.
  • the capsule will disintegrate to such an extent that it releases its carrier content which is then distributed in the vagina, causing an even distribution of the concentrate of viable lactic acid bacteria which adhere to the vaginal wall and, in the conditions prevailing in the vagina, such as temperature and moisture, will become biologically active and multiply.
  • any remainder of the carrier will tend to leave the vagina, but will not give rise to noteworthy discomfort.
  • the fluid carrier is a sub ⁇ stantially anhydrous paste preferably comprising a substantially non- hygroscopic oil which is either inherently of a suitable viscosity, e.g . comprises a mixture of oil and fat, such as cocoa butter, or which may include a particulate or dissolved or polymeric viscosity-increasing agent to obtain a suitable viscosity.
  • a suitable viscosity e.g . comprises a mixture of oil and fat, such as cocoa butter, or which may include a particulate or dissolved or polymeric viscosity-increasing agent to obtain a suitable viscosity.
  • the viscosity-increasing agent may be selected from solid or semi- solid hydrocarbons capable of forming a homogeneous system with the oil, such as vaseline or polyethylene, particulate inorganic substances such as fumed silica, talc, zeolite or bentonite, and carbohydrates or carbohydrate derivatives, preferably high molecular weight carbo ⁇ hydrates such as starch and starch derivatives . It is, however, believed to be necessary that the viscosity-increasing agents employed should have as low a water activity as possible; preferably the a does not exceed 0.1 . This means that the viscosity-increasing agent should have a certain , but limited hygroscopicity .
  • an oil and corn starch mixtu re is the preferred carrier because it has been found that there is a synergism between a sub ⁇ stantially anhydrous oil and corn starch with respect to preserving the viability of lactic acid bacteria .
  • the synergism is a combined effect of 1 ) the fact that the corn starch (which is prefe ⁇ rably in a freeze-dried or dehydrated form prior to its incorporation in the oil so as to have a water activity of almost 0: 00) has a balan ⁇ ced water activity which tends to attract water from the oil in the final system, thus competing with the dried bacterial cultu re (which is very hygroscopic in the freeze-dried state) which will also have a tendency to absorb any small amount of free water present in the oil, and 2) the starch such as corn sta rch in particular may have an inherent stabilizing effect on lactic acid bacteria .
  • the starch may advantageously be admixed with vaseline in an amount of about 10-50% by weight of the starch .
  • a combination of a sub- stantially anhydrous oil and the starch such as corn starch or, especially, the starch/vaseline mixtu re, e. g . a weight ratio in the range from about 2: 5 to about 5: 2, preferably about 1 : 1 , has been found to be a most suitable carrier for efficiently intravaginal ly administering lactic acid bacteria .
  • useful oils may be mentioned mineral or vegetable oils such as paraffin or sunflower oil .
  • the lactic acid bacteria concentrate incorporated in the capsules according to the invention may be comprised of any type of bacteria which produce lactic acid, such as bacteria belonging to the genus Streptococcus or Lactobacillus .
  • the species of Lactobacillus employed according to the invention are principally L . acidophilus, L . bulgari- cus, L . lactls, L . hefveticus, L . bifid us, L . casei , L. plantarum, L. delbrueckii , L . thermophilus or L . fermentum.
  • Preferred among Streptococcus species are S. lactis, S. cremoris, S. diacetylactis, S. thermophilus or S.
  • the lactic acid bacteria may also be incorporated in the form of a mixture of two or more of these species . Lactic acid bacteria of the species L . acidophilus have proved particu ⁇ larly advantageous . The strain of L . acidophilus which has proved to be particularly advantageous has been deposited in the Northern Regional Research Center, Peoria, USA under the accession number NRRL No. B-15260 and is publicly available.
  • the conditions treated by administering the capsule according to the invention are vulvo-vaginal infections caused by, i . a . , microorganisms such as Candida alb leans, Trichomonas vaginal is and Staphylococcus aureus as well as various anaerobic microorganisms .
  • the capsule of the invention has been found to be particularly advantageous in the treatment of recurrent vulvo-vaginal infections which has hitherto been difficult to cu re with conventional preparations such as anti ⁇ biotics.
  • a particularly advantageous species of lactic acid bacteria is L . acidophilus, as described in Example 5. The superior qualities of L .
  • acidophilus are most likely due to the fact that this species not only produces lactic acid (a decrease of pH is often not enough to control or reduce the growth of pathogenic micro ⁇ organisms) , but has also been found to produce one or more antimi ⁇ crobial metabolites described as acidophilin r vide e. g. Shahani, K. M. et al : "Natural Antibiotic Activity of Lactobacillus acidophilus and bulgaricus. 2. Isolation of Acidophilin from L, acidophilus” , Cult. Dairy Prod. J. 12, 1977, p. 8. ) , acidolin Cvide e. g . "Lactobacillus acidophilus I I . Antimicrobial agents. Cult.
  • vulvo-vaginal infections may suitably be treated by administering 1 -2 capsules a day for 3-6 days, or a similar dosage may be administered prophylactically for a few days after each men-
  • a suitable dosage in more severe cases may be 1 capsule a day until the first menstrual period, and for a 7-day period after each menstruation .
  • the capsule may be inserted with the fingers or by means of a suitable applicator.
  • the capsules may be produced by homogeneously dispersing a dried, viable, stable culture of lactic acid bacteria in a substantially an ⁇ hydrous fluid carrier, filling the resulting dispersion into soft gelatin capsules and drying the capsules after sealing.
  • the paste in order to make the mixing of the ingredients re- latively easy, especially if the paste is to include a viscosity-in ⁇ creasing agent, it is preferred to add the culture to the paste ingre ⁇ washer which has the lowest viscosity followed by adding the viscosi ⁇ ty-increasing agent in the form of other dry matter or optionally a more highly viscous ingredient.
  • This proceedu re saves time which is vital with respect to the amount of moisture taken up by the cultu re from the air.
  • an inert and dry gas may be exposed to the mixing su rface.
  • the admixture of the cultu re and optionally other dry matter and the oil may, for instance, be performed by means of a slowly operating mixer. I n this way, the uptake of air in the mixtu re is minimized, thus minimizing the risk of uptake of moistu re and oxygen which are detrimental to bacterial stability . I n order to fu rther reduce the moisture content of the final product, the ingredients are incorpo ⁇ rated in the oil in a dry state.
  • the freeze-dried bacterial concentrate has a water activity not exceeding 0.2 and preferably a far lower water activity, and when the viscosity-increasing agent employed is a starch such as corn starch , it is preferably subjected to freeze-drying prior to use, substantially to a water activity of 0.00.
  • a finely dispersed and homogeneous product is not obtained by merely mixing the ingredients as described above, and is provided e. g . by dispersing the cultu re by means of a roller mill operating at the pressu re and friction by which a fi ne division of the bacterial
  • OMPI culture is secured without, on the other hand, heating the paste or killing the bacteria .
  • the space between the rollers will normally be between 150 and 300 ⁇ m.
  • the resulting particle size will be about 100 urn.
  • the paste is gently stirred in order to impart homogeneity to the paste which is important to obtain in order to make it possible to dose accurate amounts of bacteria into each capsule.
  • the paste is then incorporated in gelatin capsules, preferably soft gelatin capsules, by a process described in US Patents Nos . 1 ,970,396, 2, 152, 101 , 2,234,479 and 2,288,327.
  • the capsules may be washed with an agent which prevents intercapsular adhesion, such as perchloroethylene, to which a lubricant such as lecithin has optionally been added whereby intercapsular adhesion and deformation of the capsules during the subsequent drying process are avoided .
  • the drying itself may be performed in a two-stage process .
  • the still wet capsules may be subjected to a strong air-flow, normally with ordinary atmospheric air with a relative humidity of about 20-60%.
  • a strong air-flow normally with ordinary atmospheric air with a relative humidity of about 20-60%.
  • the drying is continued on trays with ventilation for up to several days until the desired hardness and loss of humidity have been obtained .
  • the final product is preferably stored at a temperature below 20°C, such as at a refrigeration temperature of about 3-5°C.
  • a dry, stable, viable concentrate of L. acidophilus was prepared according to the procedures described in US Patents Nos. 4,115,199 and 3,897,307.
  • the strain of L. acidophilus used is deposited with the Northern Regional Research Center and is publicly available under the accession number NRRL No. B-15260.
  • the bacterial concentrate was dried by freeze-drying after adjusting the pH to 6.0-6.2, and the addition of 16 g L-ascorbic acid, 10 g inositol and 10 g monoso- dium glutamate per 100 g of the dry concentrate.
  • the resulting stabilized, dry concentrate contains about 1.00 x 10 11 CFU (colony- forming units) per gramme.
  • compositions stated below were prepared according to the method described above with the exception of composition C.
  • the amount of paste material varies according to the desired number of cells in the finished capsules and thus the amount of bacterial con ⁇ centrate incorporated, in order to obtain the desired viscosity.
  • Composition A A:
  • Paraffin oil of low viscosity 1 5.5 kg Freeze-dried corn starch CPC 3401 4.5 kg Freeze-dried L. acidophilus culture (1.05 x 10 1X CFU/g) 1.0 kg
  • VflPO This composition is presently preferred .
  • Composition B
  • Paraffin oil of low viscosity 1 7.0 kg yellow vaseline 2 6.0 kg L . acidophilus culture
  • Composition C is a composition having Composition C:
  • the carrier for the bacterial cultu re has as low an uptake of water as possible, and pre ⁇ ferably no uptake of water at all .
  • hygroscopicity analyses were made of the following mate ⁇ rials and mixtures of materials as shown in Table 1 .
  • the materials were spread on petri dishes with a diameter of 9 cm, and a thickness of the material of 7-8 mm, the materials having a substantially smooth surface.
  • Sunflower oil Commercial edible oil purchased from Irma. Corn starch Globe® 03401 purchased from CPC, freeze-dried to an A of 0.00. w
  • Vaseline Vaselinum Ph. Nord. 63 purchased from Meco ⁇ benzon.
  • the "white" star indicates the L . acidophilus culture alone
  • the square with the filled-in ci rcle indicates oil and viscosity- increasing agent (paraffin oil and corn starch in Fig . 1 , sunflower oil and corn starch in Fig . 2, paraffin oil and vaseline in Fig . 3)
  • the square indicates the viscosity-increasing agent alone (corn starch in Figs . 1 and 2, vaseline in Fig . 3)
  • the filled-in ci rcle indicates the oil (paraffin oil in Figs . 1 and 3)
  • the filled-in star indicates "Plastibase” (as defined above)
  • "log CFU” indicates the logarithm of colony-forming units per gramme of carrier.
  • the curves may be compared among themselves, especially with respect to the slope of the first, straight line and "breakpoint" (45°) , i. e. the temperature at which the curve changes its course (usually at 59-60°C for cultures with a satisfactory stability; indicated by the dotted line in Figs . 1 -3) .
  • the capsules have a half life of about 4 months at 20°C at which time the capsules still contain an effective amount of bacteria . Due to the improved storability at 5°C, it is, however, preferred that the capsules be stored at about 5°C or less .
  • Soft gelatin capsules were prepared according to US Patents Nos . 1 ,970,396, 2, 152, 101 , 2,234,479 and 2,288,327.
  • the capsule material may vary in composition within certain limits .
  • the composition pre ⁇ ferred for the present purpose is shown in Table 3.
  • the capsules After shaping the capsules and filling them with the dispersion of bacterial cultu re incorporated in the paste and sealing, the capsules were washed in perchloroethylene to which had been added a limited amount of lecithin in order to avoid intercapsular adhesion and defor ⁇ mation of the capsules during drying .
  • the capsules were dried for 2 hours in a rotary drier with 6-8 com ⁇ partments by a strong ai r-flow with ordinary atmospheric air with a relative humidity of about 20%. I n this manner, the capsules were dried to an extent corresponding to a loss of weight of about 40-45%. The capsules had then become sufficiently hard for continued drying
  • OMPI sy wipo to be performed on trays in a closed, ventilated cupboard at about 20°C (relative humidity 20%) for up to 4-6 days, until a suitable hardness and dessication had been obtained.
  • Each of the strains was inoculated in growth flasks with 100 ml MRS- broth to a cell count of 1 -5 x 10 s CFU/ml .
  • To some of these flasks as well as to some flasks which had not previously been inoculated were simultaneously added one of two cultu res of Candida albicans which were freshly grown from women with yeast infections (vulvo-vaginal infections) .
  • MRS-broth was inoculated with L . acidophi ⁇ lus in an amount of 5 x 10 s CFU/ml and incubated at 37°C for 24 hours after which the living cells were centrifugated off and the supernatant were finally filtered under sterile conditions .
  • the final pH was 4.18.
  • This broth was inoculated with one of the Candida cultures . All flasks were incubated at 37°C, and the broths were plated for the specific microorganism after 0 hours, 24 hours and 48 hours
  • the dotted lines represent the growth of L. acido ⁇ philus (expressed as cell count), the filled-in star indicating the growth of L. acidophilus when grown alone, and the square indicating the growth of L. acidophilus when grown together with C. albicans (two different strains in 4 a and 4 b). It appears that the growth of L. acidophilus. is not inhibited by the presence of Candida.
  • the full lines represent the growth of C. albicans, the "white” star indicating the growth of Candida when grown alone, and the circle indicating the growth of Candida when grown together with L. acidophilus. It appears that both Candida cultures are significantly inhibited (ap- prox. 4 log,,, units) when inoculated together with the L. acidophilus strain used.
  • Figs. 5 and 6 are analogous with Fig. 4 with the exception that Fig. 5 shows the use of L. bulgaricus and Fig. 6 the use of S. thermo ⁇ philus instead of L. acidophilus. From the graphs, it appears that neither L. bulgaricus nor S. thermophilus (the dotted lines) are inhibited by the growth of C. albicans. It appears from Fig. 5 that there is a slight inhibition of C. albicans when grown together with L. bulgaricus. From Fig. 6 it appears that S. thermophilus does not exert any inhibitory effect against C. albicans.
  • Fig. 7 shows that, when a broth is acidified (to a pH of 4.18 by means of the selected strain of L. acidophilus) and physically sterili ⁇ zed as described above, the C. albicans culture (indicated by the "white” circle) cannot tolerate the concentration of the antimicrobial metabolites, i.e. the cell counts drop during the first 24 hours peri- od.
  • the growth of C. albicans in normal broth is indicated by the filled-in circle.
  • a chemical acidification of MRS-broth with lactic and phosphoric acid to a pH 4-4.2 has no influence, or only very little influence, on the growth of C. albicans.
  • the study was performed at the dermatological clinic of Odense Sygehus, Denmark, involving 8 women of ages between 18 and 30 years (23 years on average) suffering from vulvo-vaginal infections, who had been referred to the clinic for treatment.
  • the test comprised administering one capsule twice daily for 7 days so that four of the patients received the capsule of the invention and four of the patients received a placebo capsule used as control.
  • a subjec ⁇ tive as well as objective evaluation of the condition of the patients was carried out, comparing it to their condition before treatment.
  • the criteria of evaluation were: recovery (scored as 1), improvement (2), no change (3), and deterioration (4).
  • the capsule according to the invention was administered once a day for 2-6 months (4 months on average) .
  • the capsule of the invention is also useful in the treatment of women suffering from severe, ch ronic or recurrent vaginitis .

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Abstract

Des capsules de gélatine solubles pour effectuer la régulation d'infections vulvo-vaginales contiennent un concentré viable, séché, stable, tel qu'un concentré lyophilisé, de bactéries d'acide lactique, en particulier le Lactobacillus acidophilus, dispersées dans un porteur fluide pharmaceutiquement actif possédant une viscosité d'au moins 2000 cps, de préférence 3000 cps, et en particulier 4000 cps. Le nombre de bactéries par capsule est d'au moins 1 x 106, de préférence au moins 1 x 107. L'activité de dilution (aw) du concentré bactérien et du porteur fluide se situe entre 0,00 et 0,2. Le porteur fluide est de préférence une huile non-hygroscopique contenant un agent d'accroissement de la viscosité comme l'amidon et/ou la vaseline. On a découvert que les capsules résultantes possédaient une activité d'inhibition envers Candida albicans in vitro et in vivo.
PCT/DK1984/000042 1983-05-27 1984-05-22 Capsules vaginales WO1984004675A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DK35685A DK35685A (da) 1983-05-27 1985-01-25 Vaginalkapsler

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DK2420/83A DK242083D0 (da) 1983-05-27 1983-05-27 Vaginalkapsler

Publications (1)

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WO1984004675A1 true WO1984004675A1 (fr) 1984-12-06

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PCT/DK1984/000042 WO1984004675A1 (fr) 1983-05-27 1984-05-22 Capsules vaginales

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EP (1) EP0147428A1 (fr)
JP (1) JPS60501160A (fr)
AU (1) AU3018684A (fr)
DK (1) DK242083D0 (fr)
WO (1) WO1984004675A1 (fr)

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987001585A2 (fr) * 1985-09-23 1987-03-26 Affiliated Innovation Management Inc. Conditionnement du vagin pour l'activite sexuelle
FR2622452A1 (fr) * 1987-10-30 1989-05-05 2 Oi Mo G Medicament a base de lactobacillus pour la prevention et le traitement des dysbacterioses vaginales
EP0353581A2 (fr) * 1988-08-05 1990-02-07 Dr. A. Tosi Farmaceutici S.R.L. Compositions pharmaceutiques contenant des souches sélectionnées de lactobacillus
DE4123330A1 (de) * 1991-07-15 1993-01-21 Gerhard Netz Verfahren zur peranalen keimapplikation
WO1993009793A1 (fr) * 1991-11-15 1993-05-27 Gregor Reid Lactobacilles et compositions lactiques maigres et procede de prevention des infections urogenitales microbiennes
EP0732916A1 (fr) * 1993-12-03 1996-09-25 Lafor Laboratories Limited Suppositoires vaginaux virucides, bactericides et spermicides
GB2310375A (en) * 1996-02-21 1997-08-27 Vanessa Clare Mcclafferty Pessaries for treating vaginal infections
US5705160A (en) * 1985-12-31 1998-01-06 Research Corporation Technologies, Inc. Lactobacillus compositions and methods for treating urinary tract infections
EP0872231A1 (fr) * 1997-04-14 1998-10-21 Dr. A. Tosi Farmaceutici S.R.L. Compositions pharmaceutiques à base de lactobacilles pour l'administration transmucosale
WO1999045099A1 (fr) * 1998-03-06 1999-09-10 Sca Hygiene Products Ab Nouvel agent
US6093394A (en) * 1997-04-11 2000-07-25 Gynelogix, Inc. Vaginal lactobacillus medicant
DE19922537A1 (de) * 1999-05-10 2000-11-16 Roland Bodmeier Darreichungsform zur Applikation in Körperöffnungen
WO2002022171A2 (fr) * 2000-09-12 2002-03-21 Pharmacia & Upjohn Company Composition pharmaceutique dotee d'une activite aqueuse specifique
WO2002028446A1 (fr) * 2000-10-03 2002-04-11 Ellen Ab Procede de production d'un article hygienique absorbant comprenant des bacteries produisant de l'acide lactique
WO2004016245A1 (fr) * 2002-08-16 2004-02-26 Mcneil-Ppc Inc. Formes posologiques vaginales semi-solides de volume optimise pour le traitement des infections vaginales
WO2004035072A2 (fr) * 2002-10-15 2004-04-29 Actial Farmaceutica, Lda. Identification et traitement d'infections vaginales
WO2006045347A1 (fr) * 2004-10-22 2006-05-04 Medinova Ag Souche de lactobacillus helveticus utile dans le traitement ou la prevention d'infections engendrees par des pathogenes urogenitaux
WO2006080035A1 (fr) * 2004-12-23 2006-08-03 Actial Farmacêutica Lda. Dispositif et methode d'identification et de traitement des affections vaginales
WO2008065492A2 (fr) * 2006-11-28 2008-06-05 Probiotical S.P.A. Composition servant à l'administration de principes biologiquement actifs dans le cadre gynécologique ou rectal et ses utilisations.
EP1965840A1 (fr) * 2005-12-22 2008-09-10 Sca hygiene products ab Article absorbant
EP1965839A1 (fr) * 2005-12-22 2008-09-10 SCA Hygiene Products AB Article absorbant
WO2008156398A1 (fr) * 2007-06-21 2008-12-24 Sca Hygiene Products Ab Article hygiénique comprenant des lactobacilli dans un support hydrophile
WO2009010368A2 (fr) * 2007-07-13 2009-01-22 Unilever N.V. Composition comprenant des bactéries et de la lécithine
EP2158916A1 (fr) * 2008-08-27 2010-03-03 Ellen Aktiebolag Unité d'administration contenant des bactéries produisant de l'acide lactique
EP2173856A1 (fr) * 2007-06-28 2010-04-14 Chr. Hansen A/S Traitement de suspension de cellules
US8158847B2 (en) 2005-12-22 2012-04-17 Sca Hygiene Products Ab Water-vapour impermeable carrier member for use in an absorbent article
WO2014009330A1 (fr) 2012-07-09 2014-01-16 S.P.M.D Nouvelle souche de lactobacillus crispatus
US8758742B1 (en) 2000-12-18 2014-06-24 Probiohealth, Llc Prebiotic and preservative uses of oil emulsified probiotic encapsulations
WO2017148975A1 (fr) 2016-03-01 2017-09-08 Biose Compositions pour le traitement des candidoses
US11202799B2 (en) 2012-07-09 2021-12-21 Probionov Use of thiosulfate to potentiate the anti-pathogenic effect of lactobacilli
US20210401879A1 (en) * 2020-06-30 2021-12-30 Vireo Systems, Inc. Compositions for controlling odor and itch and methods of and devices for administering same
WO2022172285A1 (fr) * 2021-10-18 2022-08-18 Nutra Grace Capsule vaginale à base d'huile de graines de neem pour le traitement de pertes vaginales anormales

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0761949B2 (ja) * 1990-04-25 1995-07-05 フロイント産業株式会社 腸内有用細菌含有組成物
AU4059999A (en) * 1998-06-05 1999-12-30 Wakamoto Pharmaceutical Co., Ltd. Lactic acid bacterium-containing compositions, drugs and foods
ES2681982T3 (es) * 2013-03-15 2018-09-17 Allergan Pharmaceuticals International Limited Forma de dosificación en cápsula de gelatina blanda farmacéutica

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK127268A (fr) * 1970-01-12 1900-01-01
DE605803C (de) * 1931-06-26 1934-11-19 Iwan Arbatsky Kapsel fuer Mittel zur Bekaempfung von Faeulnisprozessen im Dickdarm
DE2448648A1 (de) * 1973-10-11 1975-04-24 Dso Pharmachim Praeparat zur behandlung von gastritis, magen- und zwoelffingerdarmgeschwueren und dessen herstellungsverfahren
DE2738652A1 (de) * 1977-08-26 1979-03-15 Seiken Kai Foundational Juridi Lactobacillus-praeparat und seine verwendung zur behandlung bakterieller infektionen

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE605803C (de) * 1931-06-26 1934-11-19 Iwan Arbatsky Kapsel fuer Mittel zur Bekaempfung von Faeulnisprozessen im Dickdarm
DK127268A (fr) * 1970-01-12 1900-01-01
DE2448648A1 (de) * 1973-10-11 1975-04-24 Dso Pharmachim Praeparat zur behandlung von gastritis, magen- und zwoelffingerdarmgeschwueren und dessen herstellungsverfahren
DE2738652A1 (de) * 1977-08-26 1979-03-15 Seiken Kai Foundational Juridi Lactobacillus-praeparat und seine verwendung zur behandlung bakterieller infektionen

Cited By (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987001585A3 (fr) * 1985-09-23 1987-05-21 Affiliated Innovat Manag Inc Conditionnement du vagin pour l'activite sexuelle
US4670256A (en) * 1985-09-23 1987-06-02 V. Valhalla Corp. Vaginal conditioning for sexual activity
GB2191942A (en) * 1985-09-23 1987-12-31 Affiliated Innovat Manag Inc Vaginal conditioning for sexual activity
GB2191942B (en) * 1985-09-23 1989-12-06 Affiliated Innovat Manag Inc Vaginal conditioning for sexual activity
WO1987001585A2 (fr) * 1985-09-23 1987-03-26 Affiliated Innovation Management Inc. Conditionnement du vagin pour l'activite sexuelle
US5804179A (en) * 1985-12-31 1998-09-08 Research Corporation Technologies, Inc. Lactobacillus compositions and methods for treating urinary tract infections
US5705160A (en) * 1985-12-31 1998-01-06 Research Corporation Technologies, Inc. Lactobacillus compositions and methods for treating urinary tract infections
FR2622452A1 (fr) * 1987-10-30 1989-05-05 2 Oi Mo G Medicament a base de lactobacillus pour la prevention et le traitement des dysbacterioses vaginales
EP0353581A2 (fr) * 1988-08-05 1990-02-07 Dr. A. Tosi Farmaceutici S.R.L. Compositions pharmaceutiques contenant des souches sélectionnées de lactobacillus
US5176911A (en) * 1988-08-05 1993-01-05 Universita Cattolica Del Sacro Cuore Pharmaceutical compositions comprising selected lactobacillus strains
EP0353581A3 (en) * 1988-08-05 1990-08-01 Tosi A Farmaceut Srl Pharmaceutical compositions comprising selected lactobacillus strains
DE4123330A1 (de) * 1991-07-15 1993-01-21 Gerhard Netz Verfahren zur peranalen keimapplikation
WO1993009793A1 (fr) * 1991-11-15 1993-05-27 Gregor Reid Lactobacilles et compositions lactiques maigres et procede de prevention des infections urogenitales microbiennes
US6004551A (en) * 1991-11-15 1999-12-21 Urex Biotech, Inc. Lactobacillus and skim milk pharmaceutical compositions
US5645830A (en) * 1991-11-15 1997-07-08 Research Corporation Technologies, Inc. Lactobacillus and skim milk compositions and methods for preventing microbial urogenital infections
EP0732916A4 (fr) * 1993-12-03 1997-09-17 Lafor Lab Ltd Suppositoires vaginaux virucides, bactericides et spermicides
EP0732916A1 (fr) * 1993-12-03 1996-09-25 Lafor Laboratories Limited Suppositoires vaginaux virucides, bactericides et spermicides
GB2310375A (en) * 1996-02-21 1997-08-27 Vanessa Clare Mcclafferty Pessaries for treating vaginal infections
US6468526B2 (en) 1997-04-11 2002-10-22 Gynelogix, Inc. Vaginal lactobacillus medicant
US6093394A (en) * 1997-04-11 2000-07-25 Gynelogix, Inc. Vaginal lactobacillus medicant
US6372209B1 (en) 1997-04-11 2002-04-16 Gyne Logix, Inc. Vaginal lactobacillus medicant
EP0872231A1 (fr) * 1997-04-14 1998-10-21 Dr. A. Tosi Farmaceutici S.R.L. Compositions pharmaceutiques à base de lactobacilles pour l'administration transmucosale
WO1999045099A1 (fr) * 1998-03-06 1999-09-10 Sca Hygiene Products Ab Nouvel agent
US6761885B1 (en) 1998-03-06 2004-07-13 Sca Hygiene Products Ab Strain of Lactobacillus plantarum and uses thereof
DE19922537A1 (de) * 1999-05-10 2000-11-16 Roland Bodmeier Darreichungsform zur Applikation in Körperöffnungen
WO2002022171A2 (fr) * 2000-09-12 2002-03-21 Pharmacia & Upjohn Company Composition pharmaceutique dotee d'une activite aqueuse specifique
WO2002022171A3 (fr) * 2000-09-12 2003-01-16 Upjohn Co Composition pharmaceutique dotee d'une activite aqueuse specifique
WO2002028446A1 (fr) * 2000-10-03 2002-04-11 Ellen Ab Procede de production d'un article hygienique absorbant comprenant des bacteries produisant de l'acide lactique
US7960604B2 (en) * 2000-10-03 2011-06-14 Ellen Ab Process for production of an absorbing sanitary article comprising lactic acid producing bacteria
AU2001288185B2 (en) * 2000-10-03 2005-08-25 Ellen Ab Process for production of an absorbing sanitary article comprising lactic acid producing bacteria
US8758742B1 (en) 2000-12-18 2014-06-24 Probiohealth, Llc Prebiotic and preservative uses of oil emulsified probiotic encapsulations
GB2407504A (en) * 2002-08-16 2005-05-04 Mcneil Ppc Inc Optimal volume of intra-vaginal semisolid dosage forms for treating vaginal infections
WO2004016245A1 (fr) * 2002-08-16 2004-02-26 Mcneil-Ppc Inc. Formes posologiques vaginales semi-solides de volume optimise pour le traitement des infections vaginales
WO2004035072A2 (fr) * 2002-10-15 2004-04-29 Actial Farmaceutica, Lda. Identification et traitement d'infections vaginales
WO2004035072A3 (fr) * 2002-10-15 2004-07-08 Actial Farmaceutica Lda Identification et traitement d'infections vaginales
WO2006045347A1 (fr) * 2004-10-22 2006-05-04 Medinova Ag Souche de lactobacillus helveticus utile dans le traitement ou la prevention d'infections engendrees par des pathogenes urogenitaux
EA012488B1 (ru) * 2004-12-23 2009-10-30 Атьял Фармасеутика Лда. Приспособление и способ для идентификации и лечения вагинальных заболеваний
WO2006080035A1 (fr) * 2004-12-23 2006-08-03 Actial Farmacêutica Lda. Dispositif et methode d'identification et de traitement des affections vaginales
EP1965839A4 (fr) * 2005-12-22 2010-05-19 Sca Hygiene Prod Ab Article absorbant
US9248213B2 (en) 2005-12-22 2016-02-02 Sca Hygiene Products Ab Absorbent article
US8158847B2 (en) 2005-12-22 2012-04-17 Sca Hygiene Products Ab Water-vapour impermeable carrier member for use in an absorbent article
EP1965840A4 (fr) * 2005-12-22 2011-10-19 Sca Hygiene Prod Ab Article absorbant
EP1965840A1 (fr) * 2005-12-22 2008-09-10 Sca hygiene products ab Article absorbant
EP1965839A1 (fr) * 2005-12-22 2008-09-10 SCA Hygiene Products AB Article absorbant
WO2008065492A3 (fr) * 2006-11-28 2009-03-19 Anidral Srl Composition servant à l'administration de principes biologiquement actifs dans le cadre gynécologique ou rectal et ses utilisations.
RU2445073C2 (ru) * 2006-11-28 2012-03-20 Пробиотикал С.п.А. Композиция для введения биологически активных веществ во влагалище и прямую кишку и ее применения
WO2008065492A2 (fr) * 2006-11-28 2008-06-05 Probiotical S.P.A. Composition servant à l'administration de principes biologiquement actifs dans le cadre gynécologique ou rectal et ses utilisations.
WO2008156398A1 (fr) * 2007-06-21 2008-12-24 Sca Hygiene Products Ab Article hygiénique comprenant des lactobacilli dans un support hydrophile
EP2173856A1 (fr) * 2007-06-28 2010-04-14 Chr. Hansen A/S Traitement de suspension de cellules
US20100183768A1 (en) * 2007-06-28 2010-07-22 Karsten Baaner Treatment of cell suspension
WO2009010368A2 (fr) * 2007-07-13 2009-01-22 Unilever N.V. Composition comprenant des bactéries et de la lécithine
WO2009010368A3 (fr) * 2007-07-13 2009-03-12 Unilever Nv Composition comprenant des bactéries et de la lécithine
EP2158916A1 (fr) * 2008-08-27 2010-03-03 Ellen Aktiebolag Unité d'administration contenant des bactéries produisant de l'acide lactique
WO2010023222A1 (fr) * 2008-08-27 2010-03-04 Ellen Ab Unité d’administration comprenant une bactérie lactique
WO2014009330A1 (fr) 2012-07-09 2014-01-16 S.P.M.D Nouvelle souche de lactobacillus crispatus
US11202799B2 (en) 2012-07-09 2021-12-21 Probionov Use of thiosulfate to potentiate the anti-pathogenic effect of lactobacilli
WO2017148975A1 (fr) 2016-03-01 2017-09-08 Biose Compositions pour le traitement des candidoses
US11197899B2 (en) 2016-03-01 2021-12-14 Nexbiome Therapeutics Compositions for treating candidiasis infections
US20210401879A1 (en) * 2020-06-30 2021-12-30 Vireo Systems, Inc. Compositions for controlling odor and itch and methods of and devices for administering same
WO2022172285A1 (fr) * 2021-10-18 2022-08-18 Nutra Grace Capsule vaginale à base d'huile de graines de neem pour le traitement de pertes vaginales anormales

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AU3018684A (en) 1984-12-18
DK242083D0 (da) 1983-05-27
EP0147428A1 (fr) 1985-07-10
JPS60501160A (ja) 1985-07-25

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