WO1983001198A1 - Procede et composition de traitement d'un patient presentant des troubles sensibles a l'interferon - Google Patents

Procede et composition de traitement d'un patient presentant des troubles sensibles a l'interferon Download PDF

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Publication number
WO1983001198A1
WO1983001198A1 PCT/DK1982/000092 DK8200092W WO8301198A1 WO 1983001198 A1 WO1983001198 A1 WO 1983001198A1 DK 8200092 W DK8200092 W DK 8200092W WO 8301198 A1 WO8301198 A1 WO 8301198A1
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WIPO (PCT)
Prior art keywords
interferon
gel
composition according
composition
activity
Prior art date
Application number
PCT/DK1982/000092
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English (en)
Inventor
Kurt Frimann Berg
Kurt Baekgaard Osther
Arne M Pedersen
Bente Rose Johansen
Hans Ole Hedegaard
Birger Reinholt Moeller
Original Assignee
Kurt Frimann Berg
Kurt Baekgaard Osther
Pedersen, Arne, M.
Bente Rose Johansen
Hans Ole Hedegaard
MOLLER, Birger, Reinholt
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Kurt Frimann Berg, Kurt Baekgaard Osther, Pedersen, Arne, M., Bente Rose Johansen, Hans Ole Hedegaard, MOLLER, Birger, Reinholt filed Critical Kurt Frimann Berg
Priority to AU90518/82A priority Critical patent/AU9051882A/en
Publication of WO1983001198A1 publication Critical patent/WO1983001198A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • interferon For the last 10 years, numerous publications have been published describing the clinical usefulness of human interferons in human patients against a wide variety of diseases, such as virus infections or cancers at various stages (malignant) .
  • the basis for interferon treatment of virus infections is the antiviral activity which interferon is known to have (see, e. g. , William Stewart: The I nterferon Sy- stem, Springer Verlag, New York, 1979) . It has been reported in numerous publications that interferon also has several so-called non- antiviral activities which include the stimulation of the so-called NK system, including various killer cell systems such as M C-CML sy ⁇ stems, cell inhibitory action on cancer cells, etc. All these findings have suggested that interferon might be useful for administration to human patients suffering from virus infections or cancers or combina ⁇ tions thereof.
  • the present invention relates to a method for treating a mammal, in particular a human patient, suffering from interferon-susceptibie disorders such as pre-cancerous or cancerous tumors or local virus infections such as Herpes simplex virus infections or other disorders such as dermatitis, e. g . seborrhea, etc. , said method comprising
  • the interferon is administered topically in the proximity of a surface of the organ or site in which the interferon-susceptible disorder or condition to be treated is located.
  • the interferon will normally be applied on the exterior membrane, whereas in cases where the cell surfaces (skin or mucous membranes) are not immediately accessible, the interferon may be applied topically in a region which is in fact physically accessible to the interferon and which is as close as possible to the tumor or viral infection site.
  • the interferon is brought to act on the tumor or at the viral infection site, etc. , through a membrane-like limit which may be the skin or a mucous or serous membrane, or an endodermal or intradermal site dependent on the location of the interferon-suscep ⁇ tible disorders such as pre-cancerous or cancerous tumors or viral infections, rather than only by systemic administration to the patient.
  • interferon is applied directly to the part or parts of the body where the disease is present, and a much higher interferon concen ⁇ tration is obtained specifically in the relevant area thus establishing a more economic utilization of the interferon .
  • the interferon applied locally according to the method of the invention acts specifically and quickly, whereas syste- mic treatment might not work at all at the same interferon dosage.
  • the reason for these observed improvements is believed to be the direct access of interferon to the target organ or area in question .
  • the concentration of interferon may be 10,000 units per ml or higher in the selected area. If the same level of interferon activity were to be obtained in the same patient by means of systemic interferon administration, the patient would have to receive several billion units of interferon (such a high dosage would be harmful to the patient) .
  • a patient suffering from a certain disease and treated systemically with interferon in the same amount as used topically will often not respond, which may be due to the considerable dilution of the syste ⁇ mically applied dose as compared with the locally applied dose.
  • local injection (not according to the invention) of interfe ⁇ ron into the tumor or the target organ in question will often be undesirable because this incurs physical damage and uncontrolled release.
  • the interferon will effec ⁇ tively affect the tumor or virus-infected area even in cases where the treatment is performed for a relatively short period .
  • the lengths of these periods are in the order of weeks, which is significantly short ⁇ er than the periods normally used in or for systemic treatments (months) .
  • Organs which may be treated by the method of the invention are typically exterior or interior organs with skin or mucous or serous membrane surfaces or other membrane-like limits which are accessible without damaging vital tissue or organs of the human body.
  • Exterior skin surfaces with malignancies such as tumors, virus infec ⁇ tions or dermatitis (such as seborrhea) , itching areas, etc.
  • Skin surfaces such as mucous or serous surfaces such as the interior cavity of the nose, the mouth cavity, the external auditory duct, uterus surfaces, anal or rectal surfaces, or rectal mucosa, surfaces on penis, the anus, urethra, etc.
  • surfaces which may be treated in accordance with the invention are surfaces adjacent to cavities containing ascit ⁇ c fluids produced by tumor cells. Such surfaces may be reached by injection through tissue where any mechanical damage caused by the injection is not critical .
  • diseases which may be treated by the method of the invention are Herpes simplex, Herpes simplex genitalis. Herpes zos ⁇ ter, Herpes keratitis, Condylomata, iridocyclitis caused by a virus, pre-cancerous or cancer conditions such as dysplasia and carcinoma in situ of portio uteri or dysplasia of collum, vaginal cancers, vulva cancers, skin cancers, cell carcinomas, spi ⁇ ocellular carcinomas, cervical intraepithelial neaplacia of early stages in collum uteri and cervical cancers may also be treated.
  • abnormal skin areas itching, reddish
  • dermatitis seborrhea, etc. and possibly dandruff, are also included as disorders to be treated by the method and composition of the invention vide Example 10) .
  • the local or topical administration may be performed by applying, either directly or indirectly, a gelled interferon solution on or close to a skin surface or exterior membrane of the body or a site in which the disorder to be treated is located.
  • a gelled interferon solution on or close to a skin surface or exterior membrane of the body or a site in which the disorder to be treated is located.
  • the term "directly or indirectly" is intended to indicate that the interferon gel may be applied directly to the target as such or it may be applied close to or directly onto the membrane in question by being released from any suitable deposit form which may appropriately be applied locally or topically and which will effect a suitable release of interferon which will then be available at or close to the membrane of the organ or site to be treated .
  • the deposit is a single-phase aqueous gel containing the interferon activity.
  • the gel is transparent which is espe ⁇ cially desirable when the gel is applied on exposed skin su rfaces .
  • interferon is normally performed at a rate of from about 1-8 times a day to 1 -3 times a week.
  • This dosage administration should, of course, be adap ⁇ ted to the particular needs of the patient, the severity of the dis ⁇ ease, etc.
  • the interferon administered by the method of the invention is an interferon with relevant activity in the system of the patient to whom it is administered .
  • the interfe ⁇ ron may be selected from the group consisting of human interferon ⁇ , ⁇ , or 7 (HulFN- ⁇ , Hul FN- ⁇ , or Hu l FN-Y) , or a combination thereof, including leucocytes and human lymphoblastoid interferons or combina ⁇ tions thereof, and/or proteins which show interferon activity and which are prepared by recombinant DNA techniques.
  • the interferon may be a crude interferon, or preferably a purified interferon, e.g. a partially purified interferon (normally designated PI F in the art) , having a specific activity of about 10 6 units per mg of protein .
  • the interferon is a pure interferon protein with a specific activity of at least 10 s units per mg of protein .
  • Such pure interferon proteins and the preparation thereof are described in Berg & Heron , Scand . J . Immunol. 11 , 1980, 489-502.
  • the interferon applied is of a relatively high purity, such as a purity corresponding to about 4x10 6 International Units per mg of protein or more
  • an immunologically acceptable protein e.g. , human albumin
  • it is desirable to increase the stability of the inter ⁇ feron proteins by adding an immunologically acceptable protein , e.g. , human albumin, in a concentration on the order of 1 -2 mg of protein per ml solution used for administration with an interferon activity of 1 -4x10 s units per ml .
  • the interferon gel used according to the method of the present inven ⁇ tion may have a concentration of interferon corresponding to about 10,000 to 1 ,000,000 units per ml .
  • the administration may be perform ⁇ ed by applying the gel locally to the areas in question.
  • interferon will influence the regeneration of the cytoskeletal system of cells (e.g. transformed cells) .
  • cells ex ⁇ posed to interferon for various lengths of time will develop a more distinct cytoskeletal system compared with non- ⁇ nterferon treated cells.
  • transformed cells are, generally speaking, recog- nized as cells which have a far less organized and structured cytoske ⁇ letal system.
  • the patient undergoing the treatment according to the method of the invention should normally not be treated with any medicaments which suppress the patient ' s immunosystem, but it cannot be precluded that there are special cases where a treatment according to the method of the invention may be suitably combined with treatment with, e.g. , cell poisons (such as Methotrexate) .
  • cell poisons such as Methotrexate
  • antibiotics which do not substantial ⁇ ly inhibit the activity of interferon on the target organ may be inclu ⁇ ded in the interferon gel .
  • antibiotics should not interfere negatively with the effect of the interferon and should at the same time retain their own activity.
  • Suitable antibiotics are the tetracyclins, neomycin , gentamy- cin, polymycin B . and amfotericin B or combinations thereof .
  • the interferon gel composition may also contain a medicament known to exert inhibitory influence on the replication of Herpes simplex virus Type I and I I , such as phosphono formate, acycloguanosine, E-5-(2-bromovinyl) -2'-deoxyuridine (deoxyuridine) or 2'-fluoro-5-iodo- aracytosine (1 - (2-fluoro-2-deoxy- ⁇ -D-arabinofuranosyl-(5)-iodocytosi- ne) .
  • a medicament known to exert inhibitory influence on the replication of Herpes simplex virus Type I and I I such as phosphono formate, acycloguanosine, E-5-(2-bromovinyl) -2'-deoxyuridine (deoxyuridine) or 2'-fluoro-5-iodo- aracytosine (1 - (2-fluoro-2-deoxy- ⁇ -D-arabinofuranosyl-(5)-i
  • interferon-con- taining gel on skin surfaces which appear abnormal without being atypical cells of the said area .
  • Such areas of skin may appear as lesions .
  • the original cause for the appearance of the skin lesion is unknown (e.g. itching areas, seborrhea, dermatitis, etc) .
  • Such areas might, for example, also appear on skin surfaces of the vagina with a more or less pronounced reddish colour.
  • Interferon -con - taining gel is applied to such an area twice a week for a period of three to six weeks . Depending on the specific case, variations are to be expected in this schedule (e. g .
  • the interferon gel according to the invention may also be applied in admixture with a collagen creme.
  • This mixture may be used as a composition for treating herpes infections or for speeding up normali ⁇ zation of slightly abnormal cells located in specific areas of the skin in that the cytoskeletal structure of such cells will be strengthened subsequent to the application of such a composition .
  • the mfxed com ⁇ position comprising interferon gel and collagen creme may be especial ⁇ ly advantageous as it may be envisaged that a collagen creme admixed with the interferon gel would have an appreciable normalizing effect on the skin surfaces in question .
  • the interferon gel should preferably be of such a nature that it is capable of substantially adhering to the said membranes or skin surfaces whereby the interferon activity may diffuse from the gel into cells of the membranes or skin surfaces . It is assumed that to obtain adhesive ("sticky") property of the gel it is necessary to use a gel containing highly charged groups (positively/negatively charged) . As is generally known, the charged gels have been found to increase protein transport across biological membranes and/or to potentiate the usual action of the biologically active substance at the membrane signal level .
  • the gelling agent used for gelling the interferon solution should preferably be of such a nature that the gel may be subjected to free ⁇ zing, thawing or sterilization (e.g. by autoclav ⁇ ng at 120°C) , with retention of the single phase character and transparency of the gel .
  • Gelling agents meeting with these requirements are hydrocolloid gel ⁇ ling agents such as carbohydrates or carbohydrate derivatives, in particular a cationic or anion ⁇ c polysaccharide, especially one contain ⁇ ing COO groups, e. g . a cellulose or alg ⁇ nate derivative containing such groups, such as carboxymethyl cellulose (in particular as a salt) .
  • hydrocolloid gel ⁇ ling agents such as carbohydrates or carbohydrate derivatives, in particular a cationic or anion ⁇ c polysaccharide, especially one contain ⁇ ing COO groups, e. g . a cellulose or alg ⁇ nate derivative containing such groups, such as carboxymethyl cellulose (in particular as a salt) .
  • hydroxyethyl cellulose, methylhydroxyethyl cellulose, hydroxypropyl cellulose and methyl cellulose are examples of such a nature that it is physiologi ⁇ cally acceptable.
  • the gelling agent should be non-toxic and non-allergenic and, furthermore, it should not substantially cause changes in the normal bacterial flora of the area . Also, it should produce no undesirable side effects .
  • CMS is particularly suitable, cf. its use as a food additive for several years .
  • the gel may comprise about 4% or more of carboxymethyl cellulose.
  • interferon gels made with charged gelling agents such as carboxymethyl cellulose (CMC) have specific advanta ⁇ ges in that the interferon activity is released at a reduced rate.
  • CMC carboxymethyl cellulose
  • interferon and interferon activity are used synonymously, and no special efforts have been made to distinguish between them. This is due to the current knowledge of the properties of the interferon gel system.
  • sustained release activity of interferon as discussed above may at least theoreti ⁇ cally be explained as follows:
  • the interferon activity measured in the supernatant from the inter ⁇ feron gel may consist of soluble carboxymethyl cellulose bound to interferon .
  • the rate of release of the " interferon activity may either depend on the rate of dissolution of the CMC- interferon bonds or the release of interferon molecules from the gel or, possibly, a combination of both .
  • An advantage of the gel system (involving highly charged gels) is that it remains in contact with the surface of the target organ and will not be repelled from the target due to its ability to attach to membranes. Hence, release of the interferon will continue at the surface of the target.
  • the rate of release of the gelled solution is so adapted that the content of the interferon activity of the soluti- on is released in the course of about 4-48 hours (cf . Table 2) .
  • This is obtained by a suitable adjustment of the consistency of the gel composition, especially as regards the viscosity to obtain a gel with a viscosity of 500 - 100,000 cps at 100 RPM (Brookfield) .
  • Different viscosities may be obtained either by the amount of the gelling agent or by using different molecular weights of said agent.
  • thixotropic gels are advantageous .
  • such gels will be easy to smear and, having been applied, the gels will nevertheless show a substantially firm consistency.
  • the aqueous gel composition comprises a substance showing water retention capaci ⁇ ty, such as a physiologically acceptable humectant, for instance a polyvalent alcohol such as glycerol, propylene glycol, sorbitol, poly ⁇ ethylene glycol or ethylene glycol .
  • a physiologically acceptable humectant for instance a polyvalent alcohol such as glycerol, propylene glycol, sorbitol, poly ⁇ ethylene glycol or ethylene glycol.
  • the humectant is added to prevent the gel from drying up when applied to exterior dry skin surfaces .
  • the gel should contain a buffer substance with a pH in a range acceptable for the stability of interferon and also acceptable to the cells, in particular a buffer with a pH of about 6 - 8, in particu ⁇ lar a pH of about 7.2 - 7.5.
  • a suitable buffer solution for use in the gel is phosphate buffered saline (Dulbecco buffer) .
  • the interferon incorporated in the gel according to the invention may, as indicated above, be selected from the group consisting of human interferon ⁇ , ⁇ or . (Hul FN- ⁇ , Hu l FN- ⁇ , or Hu l FN- ⁇ ) , or a combination thereof, including human leucocyte and lymphoblastoid interferons and/or proteins which show interferon activity and which are prepared by recombinant DNA techniques .
  • the interferon may be a crude interferon, or preferably a purified interferon, e. g. a partially purified interferon (PIF) having a specific activity of about 10 6 units per mg of protein .
  • the interferon is a pure interferon protein having a specific activity of at least 10 s units per mg of protein as mentioned above.
  • the interferon incorporated in the gel is of high purity, such as a purity corresponding to 4x10 e units per mg of protein or above, it is desirable to increase the stability of the interferon proteins by adding an immunologically acceptable protein, e.g . , human albumin, in a concentration of 1 -2 mg of protein per ml .
  • an immunologically acceptable protein e.g . , human albumin
  • the amount of protein added to such interferon preparations should be in such a range that the specific activity of the final, stabilized interferon. preparation will be around 1 -4x10 6 units per mg protein .
  • the interferon-containing gel according to the invention may be prepared according to conventional principles employed to produce
  • a suitable pro ⁇ duction method comprises mixing the constituents of the gel compo ⁇ sition, sterilizing the gel composition, e.g . , by autoclaving, and aseptically mixing the gel composition with an aqueous interferon solution (e. g. PI F) , e.g . in a ratio of about 70% of gel composition to about 30% of interferon solution .
  • an aqueous interferon solution e. g. PI F
  • the concentration of interferon in the gel will normally be in the range of 5,000 - 1 ,000,000 I nternational Units/ml, preferably about 100,000 - 300,000 International Units/ml .
  • the gel composition of the invention should be stored under con ⁇ ditions securing that substantially no deterioration of the interferon activity will take place during storage. For this reason, it is often convenient to pack the interferon-containing gel in single dose con ⁇ tainers .
  • the gel is contained in a collapsible tube, the outlet of which may, if necessary, be fitted with a suitable tip for convenient application .
  • the gel may also be applied to dry surfaces using an ad ⁇ hesive provided with a cavity in which the interferon gel is placed; thus, the gel may be applied to limited areas of dry skin surfaces without being removed by, e.g. , clothes or the like.
  • the interferon gel may be placed in the cavity of the above-mentioned adhesive immediately after the preparation .
  • the adhesive is sealed in an impermeable sterile outer package which is stored.
  • This application form may be used directly and is especially suitable as it ensures an efficient utilization of the gel produced.
  • a gel base was prepared from sodiumcarboxymethyl cellulose (CMC) ad sol. limb. Pharm. Nord. 63 (8.6 g) , glycerolum eur. (20.0 g) and PBS-buffer (171 .4 g) .
  • CMC sodiumcarboxymethyl cellulose
  • the CMC was added to the cold glycerol under stirring. This mixture was added under stirring to the cold PBS-buffer, and the resulting mixture was heated in a water bath until all the CMC particles had become transparent. The resulting gel was cooled under stirring to obtain a transparent, homogeneous gel . This gel was autoclaved at 121°C, after which the mixture was cooled to about 4 C. The cooling stage between the initial heating and the autoclaving may optionally be omitted.
  • the cooled gel base was mixed with Hul FN-a(Le) PI F diluted to 700,000 units per ml under aseptic conditions .
  • the interferon gel obtained was packed in collapsible pointed tubes of aluminum, each tube con ⁇ taining 2 ml gel.
  • the tubes were stored in a freezer at a temperature of -18 C until use.
  • the viscosity was examined using a Brookfield viscosimeter Model HBT using a spindle No. RV3.
  • a methyl cellulose gel was prepared from methylcellulosum 1500 DAK (6.0 g) , glycerrolum Eur. (20.0 g) and PBS-buffer (174.0 g) in the manner described in Example 1 .
  • An interferon gel was prepared by mixing 12.5 g of the methylcel I u lo ⁇ se gel with 3.75 g of an interferon solution containing 90,000 units/ml and 1 .25 g of a Neomyc ⁇ ni solution (25 mg/ l) .
  • Example 2 200 mg of the interferon-containing gel, prepared as described in Example 1 was placed in the bottom of a test tube and 800 yliters of medium (MEM-minimal essential medium comprising 5% calf serum) was added on top of the gel . The two phases were mixed thoroughly on a Vortex for at least 30 seconds to form a suspension . It is important to secure that a finely dispersed suspension is produced. From this first dilution (1 : 5) , the usual serial dilutions (1 : 10, 1 : 100 and 1 : 1000) are performed using the above medium. The above-prepared dilutions are titrated in the usual interferon titration system as described by, e. g. , Berg, Scand . J . Immunol . 6, 1977, 77-86.
  • MEM-minimal essential medium comprising 5% calf serum
  • the stability of the interferon gel, prepared as described in Example 1 was determined by two methods :
  • OW.FI ron content in the interferon gel was performed as described above and was found to be constant over a period of several months. A titer of 130,000 - 160,000 International Units per ml of gel was found.
  • interferon gel About 0.5 ml of the interferon gel was placed in a Costar tray (about 2 cm diameter) , yielding a 2 - 3 mm thick gel layer. 2 ml medium (e.g . 5% calf serum) was carefully added on top of the gel to form a two-phase system with the interferon-containing gel at the bottom and the medium on top.
  • 2 ml medium e.g . 5% calf serum
  • 150 yliter samples were withdrawn from the upper phase at various time intervals for interferon titration at the times indicated in Table 2. Each time, 150 ⁇ liter of medium was added as a replacement.
  • a control consisting of a PI F preparation (cf. Berg & Heron, Scand. J . Immunol. 11, 1980, 489-502) was incubated under similar conditions (no gel used) .
  • the Costar tray was sealed and placed in a humidified
  • the interferon gel In order to apply the interferon gel on the area of vagina and/or uterus it is suitable to pack the interferon-containing gel in small tubes containing 1 -4 ml, preferably 2 ml of gel, under aseptic condi- tions.
  • the tubes are pointed which is considered to be advantageous for administering the interferon-containing gel to the skin surface areas of the vagina and/or cervix/uterus.
  • the interferon gel may easily be applied by squeezing the tube by hand, thus allowing the clinician properly to control the desired amount of the interferon gel used in each case (preferably ⁇ - 2 ml of the gel) .
  • For treating exterior skin surfaces (normally dry) it is advisable to use a swab.
  • ⁇ ml of the interferon-containing gel may be squeezed out of the tube and the gel is spread over the area in question by means of the swab.
  • a female monkey (weight 2 - 3 kg) had spontaneously developed a solid malignant tumor in uterus, a cancer colli uteri (and bleeding from the uterus due to ulceration) . This was verified by biopsy specimens using the usual criteria, i . e. malignant cell structures were observed in cell specimens taken several times from the uterus over a period of 5-6 months . Thus, malignant cells were clearly seen in histological samples taken from the monkey during a period of several months.
  • the monkey was treated as follows: 1 -2 million units of PI F (cf. Berg & Heron, Scand . J . Immunol . 11, 1980, 489-502) were applied directly onto the cervical duct of uterus 2-3 times weekly over a period of 6 weeks. No side effects such as toxic effects, or allergic effects were observed during this treatment. After the 6 weeks, bleedings from the uterus stopped.
  • the general health of the monkey also improved at this stage of the treatment (the 6 weeks) .
  • Several specimens from cervix uteri were taken, coded blindly, and sent to different pathologists . They were all able to verify that the specimens taken from the monkey after the 6 weeks of treatment resembled normal cells .
  • a regression/reversion had occurred (tumor cells had reverted/ regressed to normal cells) .
  • the monkey has been cured as regards the tumor origi- nally located in cervix uteri .
  • a female monkey (weight 2 - 3 kg) was treated with an interferon gel, prepared as described in Example 1 , twice a week as follows:
  • the gel covered an area of about 1 cm including the cervical orificium of the uterus. This regimen was maintained over a period of 5 weeks . No allergic reactions were ob ⁇ served.
  • the monkey had a slight redness on small parts of the portio vagina- lis uteri. Cells taken from this area were normal (no cancer cells were detected) . It was noticed that this area changed after treatment for 3 weeks using the interferon gel in that the reddish area changed into a completely normal area . Thus, it appears that lesions on the mucous membrane of the vagina or uterus may heal and revert to normal mucous membranes subsequent to such an interferon gel treatment.
  • the effect of the interferon gel improved as the treat ⁇ ment progressed in that the patient felt an itching almost instantly after the third, fourth or the fifth application of interferon gel to skin areas with unhealed Herpes simplex eruptions .
  • the interferon gel was applied 2-3 times a day on patients with pe ioral herpes; patients with Herpes zoster were treated once or twice a day, whereas patients with genital herpes were treated once a day only.
  • the treatment was initiated after the "classical" symptoms (lesions) had emerged and the treatment was in most cases continued 2-3 days after the symptoms had disappeared (the lesions had heal ⁇ ed) .
  • the topical application of the interferon gel as performed in the above test does not have a curative effect on herpes infections.
  • the treatment reduced the duration of symptoms, such as pain, markedly and accelerated the healing of lesions in patients with perioral herpes and genital herpes infection, although the efficacy of the treatment was less pronounced in the latter group. This may, highly likely, be due to the fact that the gel was applied only once a day on patients with genital herpes, but 2-3 times a day in patients with Herpes simplex.

Abstract

Procédé de traitement d'un mammifère, notamment d'un patient humain, présentant des troubles sensibles à l'interféron tels que des tumeurs pré-cancéreuses ou cancéreuses ou des infections virales locales telles que des infections virales par Herpès ou d'autres troubles tels que la dermatite, par exemple la séborrhea, etc., comprenant l'administration locale d'interféron dans une phase unique aqueuse gélifiée directement sur ou à proximité d'un organe ou de l'endroit où est situé le trouble et en continuant l'administration locale pendant une période de temps suffisante à obtenir une réponse au traitement par l'interféron. Le gel d'interféron est préparé en mélangant les constituants de gel, en stérilisant la composition de gel résistante et en mélangant aseptiquement la composition de gel avec une solution aqueuse d'interféron.
PCT/DK1982/000092 1981-10-08 1982-10-08 Procede et composition de traitement d'un patient presentant des troubles sensibles a l'interferon WO1983001198A1 (fr)

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AU90518/82A AU9051882A (en) 1981-10-08 1982-10-08 Method and composition for treating a patient suffering from interferon-susceptible disorders

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Application Number Priority Date Filing Date Title
DK4469/81811008 1981-10-08
DK446981 1981-10-08

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WO1983001198A1 true WO1983001198A1 (fr) 1983-04-14

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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2140690A (en) * 1983-05-31 1984-12-05 Schering Corp Interferon gels
EP0132754A2 (fr) * 1983-07-29 1985-02-13 The Rockefeller University Utilisation de gamma-interféron pour la fabrication d'un médicament destiné au traitement de la lèpre
EP0138216A2 (fr) * 1983-10-14 1985-04-24 Sumitomo Pharmaceuticals Company, Limited Préparation IFN à libération prolongée pour administration par voie parentérale
EP0152345A2 (fr) * 1984-02-07 1985-08-21 INTERFERON SCIENCES, INC a Delaware Corporation Excipients pour l'administration d'interféron
EP0177910A2 (fr) * 1984-10-05 1986-04-16 BIOFERON Biochemische Substanzen GmbH & Co i.K. Application de préparations contenant de l'interféron-gamma (IFN-gamma) pour le traitement systématique de différentes maladies humaines à dose réduite
US4605556A (en) * 1983-09-26 1986-08-12 Sun Star Kabushiki Kaisha Composition and method for treating erythematodes and mycosis
US4605555A (en) * 1984-09-20 1986-08-12 Sun Star Kabushiki Kaisha Composition and method for treating keratosic disorder of skin and mucosa
WO1987001288A1 (fr) * 1985-09-09 1987-03-12 Biogen N.V. Procede de traitement d'allergies
WO1987005518A1 (fr) * 1986-03-17 1987-09-24 Schering Corporation Traitement de cancers a l'aide de l'interferon gamma
EP0267684A2 (fr) * 1986-11-10 1988-05-18 Viragen, Inc. Composition d'interféron leucocytaire humain et traitement de la peau
EP0278715A2 (fr) * 1987-02-09 1988-08-17 Schering Corporation Utilisation d'interféron gamma humain pour le traitement du carcinome de cellules basales
WO1989005149A1 (fr) * 1987-12-03 1989-06-15 The Liposome Company, Inc. Compostion pharmaceutique a base de cellulose de methyle
US4855134A (en) * 1983-10-14 1989-08-08 Sumitomo Pharmaceuticals Company, Limited Sustained-release preparation
US4946674A (en) * 1984-10-05 1990-08-07 Bioferon Biochemische Substanzen Gmbh & Co. Process for treatment of rheumatic diseases
EP0392300A1 (fr) * 1989-04-11 1990-10-17 BOEHRINGER INGELHEIM INTERNATIONAL GmbH Utilisation d'au moins une cytokine pour l'obtention d'un médicament pour le traitement systémique des lésions prénéoplastiques
US5002764A (en) * 1986-08-12 1991-03-26 Schering Corporation Treatment of actinic keratoses with alpha2 interferon
US5019382A (en) * 1986-11-06 1991-05-28 The Texas A&M University System Treatment of immuno-resistant disease with low-dose interferon
US5021241A (en) * 1983-10-14 1991-06-04 Sumitomo Pharmaceuticals Company, Limited Long-term sustained-release preparation
US5200177A (en) * 1989-12-01 1993-04-06 The Children's Medical Center Corporation Treatment of atopic disorders with gamma-interferon
US5385738A (en) * 1983-10-14 1995-01-31 Sumitomo Pharmaceuticals Company, Ltd. Sustained-release injection
US5817307A (en) * 1986-11-06 1998-10-06 The Texas A&M University System Treatment of bacterial infection with oral interferon-α
JP2000506165A (ja) * 1996-03-04 2000-05-23 ザ ペン ステイト リサーチ ファウンデーション 細胞インターナリゼーションを増強するための物質および方法
WO2003053471A1 (fr) * 2001-11-07 2003-07-03 Ortho-Mcneil Pharmaceutical,Inc. Formulations aqueuses de proteines a liberation prolongee
WO2006006054A1 (fr) * 2004-07-09 2006-01-19 Universita' Degli Studi Di Roma 'tor Vergata' Elaboration d'un systeme polymere biocompatible pour liberation de substance pharmaceutique en application locale, et utilisation de ce systeme
USRE41996E1 (en) 1996-03-04 2010-12-14 The Penn State Research Foundation Massachusetts Institute of Technology Composition and methods for enhancing receptor-mediated cellular internalization

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4041152A (en) * 1973-07-27 1977-08-09 Charles Chany Pharmaceutical formulation of interferon insolubilized by fixation on a support
GB2016015A (en) * 1978-01-22 1979-09-19 Hayashibara Co Method of preparing interferon and preparations containing interferon

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4041152A (en) * 1973-07-27 1977-08-09 Charles Chany Pharmaceutical formulation of interferon insolubilized by fixation on a support
GB2016015A (en) * 1978-01-22 1979-09-19 Hayashibara Co Method of preparing interferon and preparations containing interferon

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Abstract 0476051 from MEDLINE (US National Library of Medicine accession number 81206051), Antibiotiki Vol 26(3), pp 145-9, published March 1981 (GREBENIUK V N et al) *
Int. J. Clin. Pharm. Ther. Toxicol. Vol 19, No 11. pp 498-505, published 1981, (IKIC D et al), "The clinical use of human leukocyte interferon in viral infections". *
J. Am. Acad. Dermatol. Vol 3, pp 585-95, published 1980, (YANCEY K B, SMITH G J Jr) "Interferon: Status in treatment of skin disease". *
Scheiz. Rundschau Med. (PRAXIS) Vol 68, pp 1401-05, published 1979, (FLURY F, WEGMANN T) "Klinische Erfahrungen bei der Therapie mit Interferon", see in particular p 1402, "Salbe und Gel". *
Stomatologija Moskva , Vol. 53, pp 53-55, published 1974 (abstract in English), (DROBOTKO L N et al), "Treatment with interferon ointment of acute herpetic stomatitis in children". (Russ.) *

Cited By (50)

* Cited by examiner, † Cited by third party
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GB2140690A (en) * 1983-05-31 1984-12-05 Schering Corp Interferon gels
EP0127130A3 (fr) * 1983-05-31 1986-07-02 Schering Corporation Formulations de gel à base d'interféron
EP0127130A2 (fr) * 1983-05-31 1984-12-05 Schering Corporation Formulations de gel à base d'interféron
EP0132754A2 (fr) * 1983-07-29 1985-02-13 The Rockefeller University Utilisation de gamma-interféron pour la fabrication d'un médicament destiné au traitement de la lèpre
EP0132754A3 (en) * 1983-07-29 1988-03-30 The Rockefeller University Method of diagnosis and treatment of leprosy utilizing lymphokines
US4605556A (en) * 1983-09-26 1986-08-12 Sun Star Kabushiki Kaisha Composition and method for treating erythematodes and mycosis
US4855134A (en) * 1983-10-14 1989-08-08 Sumitomo Pharmaceuticals Company, Limited Sustained-release preparation
EP0138216A2 (fr) * 1983-10-14 1985-04-24 Sumitomo Pharmaceuticals Company, Limited Préparation IFN à libération prolongée pour administration par voie parentérale
US5021241A (en) * 1983-10-14 1991-06-04 Sumitomo Pharmaceuticals Company, Limited Long-term sustained-release preparation
EP0138216A3 (en) * 1983-10-14 1985-10-30 Sumitomo Chemical Company, Limited Sustained-release preparation
US5385738A (en) * 1983-10-14 1995-01-31 Sumitomo Pharmaceuticals Company, Ltd. Sustained-release injection
US5081156A (en) * 1983-10-14 1992-01-14 Sumitomo Pharmaceuticals Company, Ltd. Sustained-release preparation
EP0152345A2 (fr) * 1984-02-07 1985-08-21 INTERFERON SCIENCES, INC a Delaware Corporation Excipients pour l'administration d'interféron
US4680175A (en) * 1984-02-07 1987-07-14 Interferon Sciences, Inc. Interferon administration vehicles
EP0152345A3 (en) * 1984-02-07 1987-09-23 Interferon Sciences, Inc A Delaware Corporation Interferon administration vehicles
US4911908A (en) * 1984-02-07 1990-03-27 Interferon Sciences, Inc. Interferon administration vehicles
US4605555A (en) * 1984-09-20 1986-08-12 Sun Star Kabushiki Kaisha Composition and method for treating keratosic disorder of skin and mucosa
US4946674A (en) * 1984-10-05 1990-08-07 Bioferon Biochemische Substanzen Gmbh & Co. Process for treatment of rheumatic diseases
EP0177910A2 (fr) * 1984-10-05 1986-04-16 BIOFERON Biochemische Substanzen GmbH & Co i.K. Application de préparations contenant de l'interféron-gamma (IFN-gamma) pour le traitement systématique de différentes maladies humaines à dose réduite
US5145677A (en) * 1984-10-05 1992-09-08 Bioferon Bichemische Substanzen Gmbh & Co. Process for treatment of diseases
EP0181455A3 (en) * 1984-10-05 1986-06-04 Bioferon Biochem Substanz Use of preparations containing gamma-interferon (ifn-gamma) for systematically treating various human diseases at a low dosage
EP0177910A3 (fr) * 1984-10-05 1986-07-02 BIOFERON Biochemische Substanzen GmbH & Co i.K. Application de préparations contenant de l'interféron-gamma (IFN-gamma) pour le traitement systématique de différentes maladies humaines à dose réduite
US5122372A (en) * 1985-09-09 1992-06-16 Biogen, Inc. Process for treatment of allergies
WO1987001288A1 (fr) * 1985-09-09 1987-03-12 Biogen N.V. Procede de traitement d'allergies
WO1987005518A1 (fr) * 1986-03-17 1987-09-24 Schering Corporation Traitement de cancers a l'aide de l'interferon gamma
US5002764A (en) * 1986-08-12 1991-03-26 Schering Corporation Treatment of actinic keratoses with alpha2 interferon
US5817307A (en) * 1986-11-06 1998-10-06 The Texas A&M University System Treatment of bacterial infection with oral interferon-α
US6372218B1 (en) 1986-11-06 2002-04-16 The Texas A&M University System Interferon dosage form and method therefor
US5019382A (en) * 1986-11-06 1991-05-28 The Texas A&M University System Treatment of immuno-resistant disease with low-dose interferon
US5824300A (en) * 1986-11-06 1998-10-20 The Texas A&M University System Treatment of neoplastic disease with oral interferon
US5830456A (en) * 1986-11-06 1998-11-03 The Texas A&M University System Treatment of viral disease with oral interferon-α
US5846526A (en) * 1986-11-06 1998-12-08 The Texas A&M University System Treatment of autoimmune disorders with oral interferon
US5882640A (en) * 1986-11-06 1999-03-16 The Texas A&M University System Treatment of hyperallergenic response with oral interferon
EP0267684A2 (fr) * 1986-11-10 1988-05-18 Viragen, Inc. Composition d'interféron leucocytaire humain et traitement de la peau
EP0267684A3 (en) * 1986-11-10 1988-11-23 Viragen, Inc. Human leukocyte interferon composition and skin treatment
EP0278715A3 (fr) * 1987-02-09 1989-03-08 Schering Corporation Utilisation d'interféron gamma humain pour le traitement du carcinome de cellules basales
EP0278715A2 (fr) * 1987-02-09 1988-08-17 Schering Corporation Utilisation d'interféron gamma humain pour le traitement du carcinome de cellules basales
WO1989005149A1 (fr) * 1987-12-03 1989-06-15 The Liposome Company, Inc. Compostion pharmaceutique a base de cellulose de methyle
EP0392300A1 (fr) * 1989-04-11 1990-10-17 BOEHRINGER INGELHEIM INTERNATIONAL GmbH Utilisation d'au moins une cytokine pour l'obtention d'un médicament pour le traitement systémique des lésions prénéoplastiques
US5200177A (en) * 1989-12-01 1993-04-06 The Children's Medical Center Corporation Treatment of atopic disorders with gamma-interferon
JP2000506165A (ja) * 1996-03-04 2000-05-23 ザ ペン ステイト リサーチ ファウンデーション 細胞インターナリゼーションを増強するための物質および方法
USRE41996E1 (en) 1996-03-04 2010-12-14 The Penn State Research Foundation Massachusetts Institute of Technology Composition and methods for enhancing receptor-mediated cellular internalization
USRE42012E1 (en) 1996-03-04 2010-12-28 The Penn State Research Foundation Compositions and methods for enhancing receptor-mediated cellular internalization
USRE42072E1 (en) 1996-03-04 2011-01-25 The Penn State Research Foundation Compositions and methods for enhancing receptor-mediated cellular internalization
EP0885002B1 (fr) * 1996-03-04 2011-05-11 The Penn State Research Foundation Materiaux et procedes permettant d'accroitre la penetration intracellulaire
WO2003053471A1 (fr) * 2001-11-07 2003-07-03 Ortho-Mcneil Pharmaceutical,Inc. Formulations aqueuses de proteines a liberation prolongee
US6818613B2 (en) 2001-11-07 2004-11-16 Ortho-Mcneil Pharmaceutical, Inc. Aqueous sustained-release formulations of proteins
AU2002343666B2 (en) * 2001-11-07 2007-04-05 Ortho-Mcneil Pharmaceutical, Inc. Aqueous sustained-release formulations of proteins
US7282480B2 (en) 2001-11-07 2007-10-16 Ortho-Mcneil Pharmaceutical, Inc. Aqueous sustained-release formulations of proteins
WO2006006054A1 (fr) * 2004-07-09 2006-01-19 Universita' Degli Studi Di Roma 'tor Vergata' Elaboration d'un systeme polymere biocompatible pour liberation de substance pharmaceutique en application locale, et utilisation de ce systeme

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