JP4531141B2 - Drug delivery device and method for the treatment of viral and microbial infections and debilitating syndrome - Google Patents

Description

1. Field of Invention
The present invention relates to animals infected with viral or microbial infections, in particular retroviruses such as HIV, by administering a highly polar compound such as N, N′-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO), Or it relates to the treatment of animals suffering from wasting syndrome, in particular from wasting syndrome associated with HIV infection or malignancy. The present invention also provides pharmaceutical preparations and drug delivery devices comprising highly polar compounds such as DMF or DMSO for use in the treatment of animals suffering from viral or other microbial infections or debilitating syndrome.
2. Background of the Invention
2.1 Human immunodeficiency virus
Human immunodeficiency virus (HIV) induces persistent and progressive infection and most often progresses to acquired immunodeficiency syndrome (AIDS) (Barre-Sinoussi et al., 1983, Science 220: 868-870; Gallo et al., 1984, Science 224: 500-503). At least two types of HIV, namely HIV-1 (Barre-Sinoussi et al., 1983, Science 220: 868-870: Gallo et al., 1984, Science 224: 500-503) and HIV-2 (Clavel et al., 1986, Science 223: 343-346; Guyader et al., 1987, Nature 326: 662-669). HIV replication in humans is mainly CD4⁺When it occurs in T lymphocytes and is infected with HIV, this cell type is depleted, resulting in immune dysfunction, opportunistic infections, neurological dysfunction, tumor growth, and ultimately death.
HIV belongs to the lentivirus subfamily of retroviruses (Teich et al., 1984, edited by RNA Tumor Viruses, Weiss et al., CSH-press, pp. 949-956). Retroviruses are small, enveloped viruses that have a single-stranded RNA genome and are replicated via DNA-encoded reverse transcriptase, a DNA intermediate made by RNA-dependent DNA polymerase (Varmus H., 1988, Science 240: 1427-1439). Retroviruses include other oncogenic viruses such as human T-cell leukemia virus (HTLV-I, -II, -III) and feline leukemia virus.
The HIV virion consists of a viral core that forms part of the capsid proteins designated p24 and p18, and a viral RNA genome and enzymes that require early replication. The myristinated gag protein constitutes the outer viral shell surrounding the viral core, while the viral shell is surrounded by a lipid membrane envelope derived from the infected cell membrane. The glycoprotein on the surface of the HIV envelope is synthesized as a 160 KD single precursor protein, which is then cleaved by intracellular proteases during the process of virus germination into two types of glycoproteins gp41 and gp120. gp41 is an transmembrane glycoprotein, and gp120 is an extracellular glycoprotein that exists as a trimer or multimer by non-covalent bonding with gp41 (Hammerskjold, M. and Rekosh, D., 1989, Biochem). Biophys. Acta 989: 269-280).
HIV, like other enveloped viruses, introduces viral genetic material into host cells via viral envelope-mediated fusion of the viral and target membranes. Since CD4 cell surface protein (CD4) acts as an intracellular receptor for HIV-1 virus, HIV is CD4⁺Target cells (Dalgleish et al., 1984, Nature 312: 763-767; Klatzmann et al., 1984, Nature 312: 767-768; Maddon et al., 1986, Cell 47: 333-348). Virus entry into the cell depends on gp120 binding to intracellular CD4 receptor molecules (Pal et al., 1993, Virology 194: 833-837; McDougal et al., 1986, Science 231: 382-385, Maddon et al., 1986, Cell 47: 333-348) explains the fertility of HIV to CD4 cells. On the other hand, gp41 is fixed to the envelope glycoprotein complex in the virus membrane. The binding of gp120 to CD4 induces a conformational change in the viral glycoprotein, but this binding alone is insufficient to lead to infection (Review of Sattentau and Moore, 1993, Philos. Trans. R. Soc. London (Biol.) 342: 59-66).
Studies of isolated HIV have found heterogeneity in the ability to infect various human cells (Miedema et al., 1994, Immunol. Rev. 140: 35-72). Most of the HIV-1 experimental strains that had been extensively transferred were easily infected with the primary and primary T lymphocytes, but no infection was observed with primary cultures or macrophages. These strains are referred to as T-tropic. The T-tropic HIV-1 strain is considered to have a high probability of being detected from HIV-1 infected individuals in the late stage of AIDS (Weiss et al., 1996, Science 272: 1885-1886). Primary isolates of HIV-1 (ie, viruses that have not been extensively inherited) replicate effectively in primary cultured lymphocytes, monocytes, and macrophages, but grow poorly in serially cultured T cell lines. These isolates are called M-tropics. Viral T- and M-fertility determinants have been mapped to change the third variable region (V3 loop) of gp120 (Choe et al., 1996, Cell 85: 1135-1148; Cheng-Mayer et al., 1991, J. Virol. 65: 6931-6941; Hwang et al., 1991, Science 253: 71-74; Kim et al., 1995, J. Virol., 69: 1755-1761; O'Brien et al., 1990, Nature 348: 69-73). The characteristics of HIV isolates with clear fertility and the finding that they bind only to CD4 cell surface proteins are not sufficient to lead to infection, and CD4 It also suggests that a co-factor specific to the cell type is required.
2.2 Treatment of HIV infection
HIV infection is a global epidemic, and HIV-related diseases are one of the major global health problems. Despite great efforts to design effective treatments, there are currently no antiretroviral agents against AIDS. In an attempt to develop such drugs, several stages of the HIV life cycle are considered as targets for therapeutic intervention (Mitsuya, H. et al., 1991, FASEB J. 5: 2369-2381). Since host cell protein interference is widely considered to have deleterious side effects, many viral targets have been proposed for intervention in the HIV life cycle. For example, virus-encoded reverse transcriptase is considered the focus of drug development. A number of reverse transcriptase targeted drugs including 2 ′, 3′-dideoxynucleoside analogues such as AZT, ddI and d4T have been developed and found to have activity against HIV (Mitsuya, H. et al. Et al., 1991, Science 249: 1533-1544).
Anti-HIV compounds such as azidothymidine (AZT), lamivudine (3TC), dideoxyinosine (ddI), dideoxycytidine (ddC) and HIV-1 protease targeting a reverse transcriptase (RT) with a new HIV-1 therapy In combination with inhibitors, it has been observed that it is much more effective against viral load (2-3 log reduction) compared to AZT alone (about 1 log reduction). For example, impressive results have recently been obtained with the combination of AZT, ddI, 3TC and Ritonavier (Perelson, A.S. et al., 1996, Science 15: 1582-1586). However, when these compounds are used in combination over a long period of time, toxicity, particularly toxicity to the bone marrow, may appear. In addition, after long-term cytotoxic therapy, killer cell activity (Blazevic, V., et al., 1995, AIDS Res. Hum. Retroviruses 11: 1335-1342) and inhibitors, especially chemote lantes, CD8 essential for the control of HIV by the supply of MIP-1α and MIP-1β (Cocchi, P., et al., 1995, Science 270: 1811-1815)⁺T cell suppression occurs. Another major problem with long-term chemical antiretroviral therapy is the development of HIV mutations with partial or complete resistance (Lange, J.M., 1995, AIDS Res.Hum.Retroviruses 10: S77-82). Such mutations are considered unavoidable in antiviral therapy. Disappearance of wild-type virus with treatment and emergence of mutant virus, accompanying CD4⁺The pattern of T cell reduction is at least for some compounds, the emergence of viral variants is a major cause of AIDS treatment failure.
Attempts have also been made to develop drugs that inhibit the entry of viruses into cells at the earliest stages of HIV infection. In this case, the focus is on CD4, the HIV receptor on the cell surface. For example, CD4 by some HIV-1 strains with recombinant soluble CD4⁺It has been observed to inhibit T cell infection (Smith, D.H., et al., 1987, Science 238: 1704-1707). However, certain primary HIV-1 isolates are relatively insensitive to inhibition by recombinant CD4 (Daar, E., et al., 1990, Proc. Natl. Acad. Sci. USA 87: 6574- 6579). Furthermore, in clinical trials using recombinant soluble CD4, no clear results were obtained (Schooley, R., et al., 1990, Ann. Int. Med. 112: 247-253; Kann, JO, et al., 1990 Ann. Int. Med. 112: 254-261; Yarchoan, R., et al., 1989, Proc. Vth Int. Conf. On AIDS, p. 564, MCP 137).
As a potential target for anti-HIV drugs, a late stage of HIV replication has been proposed in which a critical virus-specific synthesis of certain viral encoded proteins takes place. Late-stage synthesis depends on the activity of viral proteases, and drugs that inhibit this protease have been developed (Erickson, J., 1990, Science 249: 527-533).
Recently, CD8⁺Chemokines produced by T cells have been found to suppress HIV infection (Paul, W.E., 1994, Cell 82: 177; Bolognesi, D.P., 1993, Semin. Immunol. 5: 203).
CD8⁺The chemokines Rantes, MIP-1α and MIP-1β secreted by T cells are found to suppress HIV-1 p24 antigen production in cells infected with HIV-1 or HIV-2 isolates in vitro. (Cocchi, F. et al., 1995, Science 270: 1811-1815).
Thus, although these and other chemokines appear to prove useful in the treatment of HIV infection, the results of all these and other candidate drug clinical trials remain questionable.
Attempts have also been made to develop vaccines for use in the treatment of HIV infection. The major antigen of anti-HIV antibodies present in AIDS patients has been found to be HIV-1 envelope proteins (gp160, gp120, gp41) (Batin et al., 1985, Science 228: 1094-1096). Thus, these proteins appear to be the best candidates as antigens for anti-HIV vaccine development. Various proteins of gp160, gp120 and / or gp41 have begun to be used by several research groups as immunogenic targets of the host immune system. See, for example, Ivanoff, L., et al., US Pat. No. 5,141,867, Saith, G., et al., WO92 / 22,654; Shafferman, A., WO91 / 09,872; Formoso, C., et al., WO90 / 07,119. However, since viruses are rapidly mutated and many of these vaccines lose their effectiveness, vaccines targeting HIV proteins also have problems. However, the clinical results of these candidate vaccines will be obtained in the future.
Despite great efforts in the design and testing of antiretroviral agents, effective and non-toxic treatments remain desirable.
2.3 Wasting syndrome
Wasting syndrome is a clinically serious problem characterized by a weight loss of more than 10% from the original weight and a weight loss that is not proportional to body fat (Weinroth et al., 1995, Infactious Agents and Disease 4:76 -94; Kotler and Grunfeld, 1995, AIDS Clin. Rev. 96: 229-275). Thus, depletion can be distinguished from starvation, in which a reduction in body fat is more pronounced than somatic cell mass (Kotler et al., 1985, Am. J. Clin. Nutr. 42: 1255-1265; Cahill, 1970, N.Engl.J.Med.282: 668-675). Wasting is associated with many conditions such as HIV infection, other infectious diseases, sepsis, cancer, chronic cardiovascular disease, and diarrhea (Kotler et al., 1989, Am. J. Clin. Nutr. 50: 444- 447; Heymsfield et al., 1982, Am. J. Clin. Nutr. 36: 680-690). Importantly, exhaustion is a significant cause of death in infected or cancer patients. In fact, there is a linear correlation between somatic cell mass loss and survival in AIDS patients (Kotler et al., 1989, Am. J. Clin. Nutr. 50: 444-447).
The cause of debilitating syndrome in AIDS and other conditions is not clear but appears to be not a single factor. In the debilitating syndrome, metabolic abnormalities, irregular hormone concentrations, cytokines and malabsorption are all recognized. Since not all AIDS patients suffer from exhaustion, it is thought that the cause of exhaustion is not HIV itself. Most of the debilitating syndrome associated with HIV is apparently due to comorbid AIDS such as secondary infection and gastrointestinal tract disease (Kotler and Grunfeld, 1995, AIDS Clin. Rev. 96: 229-275).
Treatment methods for debilitating syndrome, including those currently in progress, include nutritional supplements, appetite enhancers such as dronabinol and mogestol acetate, anabolic therapies such as growth hormone, and cytokin inhibitors. However, nutritional supplements and appetite-enhancing agents yielded miscellaneous results, and the patient tended to increase only fat, with no increase in overall somatic mass. Administration of growth hormone and cytokin inhibitors is currently being tested but may cause side effects (Kotler and Grunfeld, 1995, AIDS Clin. Rev. 96: 229-275; Weinroth et al., 1995, Infectious Agents and Disease 4: 76-94)
Therefore, the treatment of exhaustion is essential for the survival and well-being of patients suffering from serious diseases such as cancer and AIDS, and a safe and effective treatment for debilitating syndrome associated with cancer, AIDS and other infectious diseases Is desired.
2.4 Properties of dimethylformamide and other polar compounds
N, N'-dimethylformamide (DMF) (molecular formula C_ThreeH₇ON) is a highly polar, colorless hygroscopic liquid with low volatility and a boiling point of 152.5-153.5 ° C. Soluble in water, alcohols and certain hydrocarbon solvents. DMF is widely used as a polar solvent and is easily absorbed by transdermal, inhalation and ingestion. DMF is rapidly metabolized, particularly in the liver, and is excreted primarily in the urine. The major metabolites of DMF in rats, mice, hamsters and humans are N-hydroxymethyl-N-methylformamide (HMMF), N-methylformamide (NMF), N-acetyl-S- (N-methylcarbamoyl) cysteine (AMCC), and dihydroxymethylformamide (DHMF) and N-hydroxymethylformamide (HMF). Part of the administered DMF is excreted in the urine as unchanged DMF.
The acute dermal, oral and inhalation toxicity of DMF is weak. Has mild to moderate skin and eye irritation and easily penetrates the skin. The target organ for toxicity of DMF and its metabolites is the liver, causing reversible liver damage with typical clinical complaints, classic blood biochemical changes and hepatocyte necrosis seen in liver biopsies It has been known. DMF is considered teratogenic but not mutagenic or carcinogenic.
Viza et al. Report that DMF and DMSO inhibit replication of HIV and human herpesvirus 6 (HHV-6) in certain cultured cell lines in vitro (Viza et al., 1990, AIDS Res. Hum. Retroviruses 6: 131-132; Viza et al., 1989, AIDS-FORSCHUNG 4: 349-352; see Viza et al., 1992, Antiviral Res. 18: 27-38 and 19: 179 typographical correction).
DMF is known as an in vitro sorting agent for certain transformed cells in cultured cells (see Koeffler, 1983, Blood 62: 709-721; Calabresi et al., 1979, Biochem. Pharmacol. 28: 1933-1941). ). In vitro addition of DMF to certain malignant cells has been reported to reduce its tumorigenicity even when inoculated into nude mice (Dexter, 1977, Cancer Res. 37: 3136-3140; Dexter et al., 1979, Cancer Res. 39: 1020-1025). Intraperitoneal injection of DMF and NMF has been reported to reduce the growth of certain human carcinoma xenografts (Van Dongen et al., 1989, Int. J. Cancer 43: 285-292; Braakhuis et al. 1989, Head & Neck 11: 511-515; Van Dongen et al., 1988, Acta Otolaryngolo. 105: 488-493; Dexter et al., 1982, Cancer Res. 42: 5018-5022). However, due to the toxic side effects of formaldehyde and its N-methyl derivative in a mouse sarcoma allograft model, researchers determined that the therapeutic utility of these drugs could not be demonstrated. (Clarke et al., 1953, Proc. Sec. Exp. Biol. Med. 84: 203-207).
It has been reported that treatment of human cancer patients with DMSO was attempted and no objective response was observed (see Spremulli & Dexter, 1984, J. Clin. Oncol. 2: 227-241). Oral administration of NMF to human patients with cancer in the head and neck shows liver toxicity and no beneficial response (see Vogel et al., 1987, Invest. New Drugs 5: 203-206) Only a slight activity has been observed (see Planting et al., 1987, Cancer Treat Rep. 71: 1293-1294).
U.S. Pat. No. 3,551,154 discloses the use of DMF as a permeation enhancer to promote transdermal absorption of topically treated drugs. US Pat. No. 4,855,294 discloses the use of DMSO used as a permeation enhancer to promote percutaneous absorption of topically treated drugs and the use of glycerin to reduce skin irritation by DMF. Woodford & Barry (1986) reports the use of DMSO as a permeation enhancer to promote percutaneous absorption of antiviral agents (J. Toxicol. Cut. & Ocular Toxicol. 5: 167-177). .
Citation or description of a reference made in section 2 (or other section) of this specification is not an admission that these citations exist as prior art to the present invention.
3. Summary of invention
The present invention relates to methods, compositions and drug delivery devices for use in the treatment of animals affected by infection with viruses or other microorganisms, particularly infection with retroviruses such as HIV. The present invention also provides methods, compositions and drug delivery devices for use in the treatment of animals exhibiting debilitating syndrome such as wasting associated with HIV infection or malignancy.
According to the present invention, N, N′-dimethylformamide (dimethylformamide, DMF), N-hydroxymethyl-N-methylformamide (HMMF), N-hydroxymethylformamide (HMF), dihydroxymethylformamide (DHMF), N- Acetyl-S- (N-methylcarbamoyl) cysteine (AMCC), N-methylformamide (NMF), dimethyl sulfoxide (DMSO), formamide, acetamide, methylacetamide, dimethylacetamide, diethylacetamide, isopropylacetamide, diisopropylacetamide, N- Acetylpiperidine, N- (β-hydroxyethyl) acetamide, N, N′-di- (β-hydroxyethyl) acetamide, N-acetylmorpholine, acrylamide, Ropionamide, N-fluoromethyl-N-methyl-formamide, pyridine-N-oxide, or the general formula R_Three-CO-NR₁R₂(Where R₁And R₂Each independently represents H, methyl, halomethyl, saturated or unsaturated C₂-C_ThreeSelected from the group consisting of alkyl groups, and hydroxylated alkyl groups, or R₁And R₂Together (CH₂)_Four, (CH₂)_Five, And (CH₂)₂O (CH₂)₂Selected from the group consisting of and R_ThreeIs H, methyl, halomethyl, and saturated or unsaturated C₂-C_ThreeSelected from the group consisting of alkyl groups. A composition comprising a compound selected from the group consisting of amides represented by formula (1) is administered to an animal in need of treatment. The therapeutic composition may be a mixture of two or more of the above compounds.
Therapeutic compositions for use in HIV patients are optionally limited to the compositions of the present invention, including, but not limited to, nucleoside analog reverse transcriptase inhibitors, non-nucleoside analog reverse transcriptase inhibitors, and protease inhibitors. It may be used in combination with one or more other drugs effective for the treatment of HIV selected from the group consisting of drugs.
The present invention also includes a vaccine prepared from an antibody obtained from the body of an animal treated with the composition for treating viral infection of the present invention.
4). Brief description of the figure
The present invention can be more fully understood with reference to the following detailed description, examples, and accompanying drawings. here,
FIG. 1 shows the time course of plasma DMF concentration in 4 patients patched with DMF for 8 hours on two skins.
FIG. 2 shows the time course of plasma DMF concentration in 3 patients patched with DMF on the skin at 2 locations for 6 hours.
FIG. 3 shows the HIV-1 viral load measured by quantitative PCR for 3 patients treated with DMF transdermally. DMF patches were performed at 2 locations on the forearm for 12 hours on Trials 0, 8, and 13 (indicated by arrows).
FIG. 4 shows the general status of HIV-infected patients evaluated according to Karnofsky performance evaluation scores before and after DMF transdermal treatment. See section 7 for details.
5. Detailed Description of the Invention
The present invention provides methods, compositions and drug delivery devices for use in the treatment of viruses and microbial infections. According to the examples, the infections to be treated are retroviruses such as HIV, including asymptomatic infections, latent infections, infections with one or more symptoms of AIDS-related complications, and infections with clinical AIDS It is infection by. Otherwise, the infection to be treated is rubella, herpesvirus such as human herpesvirus 6, infection with EB virus or cytomegalovirus, infection with any virus having a capsid protective film, acquired system such as acquired infection in HIV-infected patients Other viral or microbial infections, including any acquired infection with disease.
The present invention also provides methods, compositions and drug delivery devices for treating or preventing any disease or disorder characterized by decreased body mass. Specific conditions that can be treated with the methods and compositions of the present invention include viruses (eg, HIV), bacteria, or other types of infection or sepsis, cachexia associated with malignant disease, chemotherapy or radiation therapy. This includes, but is not limited to, related exhaustion, exhaustion associated with chronic cardiovascular disease, exhaustion from exposure to toxic or radioactive substances, and diarrhea and other gastrointestinal disorders.
The subject of treatment is any animal, including monkeys, dairy cows, sheep, steers, pigs, horses, cats, dogs, chickens, etc., preferably mammals, more preferably human adults or infants, eg weighing at least 3 kg. However, the present invention is not limited to these. As used herein, “patient” means any animal in need of treatment with a method or composition according to the present invention.
According to the present invention, DMF, HMMF, HMF, DHMF, AMCC, NMF, DMSO, formamide, acetamide, methylacetamide, dimethylacetamide, diethylacetamide, isopropylacetamide, diisopropylacetamide, N-acetylpiperidine, N- (β-hydroxy Ethyl) acetamide, N, N′-di- (β-hydroxyethyl) acetamide, N-acetylmorpholine, acrylamide, propionamide, N-fluoromethyl-N-methyl-formamide, pyridine-N-oxide, general formula R_Three-CO-NR₁R₂(Where R₁And R₂Are each independently H, methyl, halomethyl, saturated or unsaturated C₂-C_ThreeSelected from the group consisting of an alkyl group and a hydroxylated alkyl group;_ThreeIs H, methyl, and saturated or unsaturated C₂-C_ThreeSelected from the group consisting of alkyl groups. Or a compound selected from the group consisting of amides represented by formula (R):_Three-CO-NR₁R₂(Where R₁And R₂Are each independently H, methyl, halomethyl, saturated or unsaturated C₂-C_ThreeSelected from the group consisting of alkyl groups and hydroxylated alkyl groups, or R₁And R₂Together (CH₂)_Four, (CH₂)_Five, And (CH₂)₂O (CH₂)₂R selected from the group consisting of_ThreeIs H, methyl, halomethyl, and saturated or unsaturated C₂-C_ThreeSelected from the group consisting of alkyl groups. A therapeutic composition comprising a compound selected from the group consisting of amides represented by
According to one embodiment of the present invention, R₁And R₂At least one of is a methyl group. According to another embodiment, R₁And R₂At least one of the fluorinated C₁-C_ThreeIt is an alkyl group. The therapeutic composition may be a mixture of two or more of the above compounds. A particularly preferred composition is a composition comprising DMF.
Compositions for use in the treatment of HIV-infected animals optionally include the composition of the present invention and one or more agents effective in the treatment of HIV infection, such as azidovudine (AZT, ZDV), zalcitabine (ddC) One or more non-nucleoside analogues such as one or more nucleoside-related reverse transcriptase inhibitors, nevirapine, delavirdine, lobilide, atebirdin, pyridinone, etc., didanosine (ddI), lamivudine (3TC), stavudine (d4T), etc. A reverse transcriptase inhibitor, saquinavir, indinalvir, ritonavir, nelfinalvir and the like may be used in combination with one or more protease inhibitors or any mixture of the above or other anti-HIV therapeutics. The compositions of the present invention and other anti-HIV therapeutics or mixtures thereof can be administered simultaneously, sequentially or in cycles according to the desired therapeutic protocol.
The compositions of the invention are administered by any desired route, such as enteral or parenteral, such as transdermal, intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, intranasal, epidural, intralymphatic and oral routes. However, it is not limited to these. The composition may be administered by conventional methods such as infusion or mass injection, absorption from epithelial or mucosal lining (eg oral mucosa, gastric mucosa, intestinal mucosa, rectal mucosa, etc.) It may be administered together with a physiologically active substance.
Administration can be systemic or local. Furthermore, it may be desirable to supply the pharmaceutical composition of the present invention to the central nervous system by an appropriate route, such as intraventricular and intratracheal injection. Intraventricular injection can be performed with a ventricular catheter connected to a reservoir, such as, for example, an Ommaya reservoir. Alternatively, the preparation may be mixed with an aerosol and administered to the pulmonary artery using, for example, an inhaler or a nebulizer. If necessary, two or more routes of administration may be used, and simultaneous, sequential or cycle administration may be performed according to the treatment protocol.
In another example, it may be desirable to administer the composition of the present invention to a local area in need of treatment. This may be done, for example, by topical treatment, injection, catheter, suppository, implant, but is not limited thereto. Said implants are made of a porous, non-porous or gelatinous material comprising a membrane or fiber such as a shearable membrane.
According to another embodiment, the composition of the present invention can be supplied to vesicles, particularly liposomes (Langer, 1990, Science 249: 1527-1533; Treat et al., Therapy of Infectious Disease and Cancer, Lopez-Berestein). & Fidler, Liss, 1989, New York, pp. 353-365; see Lopez-Berestein, ibid., Pp. 317-327.
According to yet another embodiment, the compositions of the present invention can be delivered using a sustained release system.
In certain embodiments, a pump can be used (Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14: 201; Buchwald et al., 1980, Surgery 88: 507; Saudek et al., 1989, N. Engl.J.Med.321: 547). According to another embodiment, polymeric materials can also be used (Medical Applications of Controlled Release, edited by Langer & Wise, CRC Pres., Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance. Smolen & Ball, Wiley, New York (1984); Ranger & Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61; Levy et al., 1985, Science 228: 190; During et al., 1989 , Ann. Neurol. 25: 351; Howard et al., 1989, J. Neurosurg. 71: 105). According to another embodiment, a sustained release system can be implanted near the treatment site and a portion of the systemic dose can be used (Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115 -138, 1984).
A review by Langer (Science 249: 1527-1533, 1990) discusses another sustained release system.
Furthermore, the present invention provides pharmaceutical preparations. The preparation consists of a therapeutically effective amount of the composition of the invention and a pharmacologically acceptable carrier. According to embodiments of the present invention, the term “pharmacologically acceptable” is approved by federal or state regulatory agencies for use on animals, particularly humans, or is commonly recognized by the United States Pharmacopeia or others. It means that it is described in the pharmacopoeia. “Carrier” refers to a diluent, adjuvant, adjuvant or solvent used to administer the composition of the invention. Such pharmaceutical carriers include those derived from sterilized liquids such as water and oil, petroleum, animal, plant or synthetic such as peanut oil, soybean oil, mineral oil and sesame oil. Water is preferred as the carrier when the pharmaceutical preparation is administered intravenously. Saline, aqueous dextrose and glycerol solutions can also be used as liquid carriers, in particular as injection carriers. Adjuncts suitable as pharmaceuticals are starch, glucose, lactose, fructose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, polyethylene glycol, Water, ethanol and the like. The pharmaceutical preparation may contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as required. These preparations may be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations and the like. The preparation may be formulated in a suppository with conventionally used sticking agents and carriers such as triglycerol. Oral formulations may contain standard carriers such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, saccharin, cellulose, magnesium carbonate and the like. Suitable carriers are described in “Reminton's Pharmaceutical Sciences” by E.W.Martin. The preparation may comprise a therapeutically effective amount of a therapeutic agent, preferably in purified form, together with a suitable amount of carrier, and may be in a form suitable for administration to a patient. The formulation should be suitable for the mode of administration.
The composition of the present invention may be administered transdermally. According to an embodiment of the present invention, the composition of the present invention is administered directly to the skin. According to another embodiment, the composition of the present invention is a reservoir (eg, cotton pad, teflon).^TMOr other suitable absorbent material) and affix it to the skin, preferably under an occlusive dressing. According to another embodiment, the composition of the present invention is applied to the skin using a skin patch. The active ingredient concentration in the composition when applied to the skin, absorbed in the reservoir or absorbed into the reservoir, or added to the skin patch is about 10-100%, desirably at least 50%, more desirably at least 90%. %.
In a preferred embodiment, polar compounds such as DMF are administered transdermally using a suitable drug delivery device, for example by applying a skin patch in one or several places. If necessary, the skin patch may be composed of a permeable membrane to be adhered to the skin and a reservoir such as an absorbent material impregnated with the polar compound of the present invention. As the back, any material such as a natural or synthetic polymer can be used as long as it is not chemically changed by the polar compound. Particularly preferred is the back of high density polyethylene. The absorbent material may be a colloidal material such as diatomaceous earth or colloidal silicon dioxide. The permeable membrane may be any material that is chemically stable to the polar compound, and may be porous if necessary. According to a preferred embodiment, the permeable membrane has a pore size in the range of about 0.1 μm or about 0.5 μm, or about 0.1 to about 0.5 μm.^TMIt is a membrane. The patch may be adhesive or may be adhered to the skin with an applicator such as a wrapping material or bandage including but not limited to stretch bandages or adhesive bandages. Preferably, the patch contains more polar compound than is desired to be delivered from the subject patient's skin. For example, the patch contains about 50% more polar compound than is desired to be delivered. The size and shape of the patch may be as desired, for example, a disk having a diameter of about 9 cm.
According to one embodiment of the invention, the patch comprises a polar compound such as DMF and at least one other pharmacologically active ingredient, for example an anti-local stimulant such as glycerin. According to another embodiment, the patch contains a polar compound such as DMF and no other pharmacologically active ingredients. According to yet another embodiment, the patch contains a polar compound, such as DMF, but a pharmacologically active ingredient that is absorbed systemically from the skin or an amount sufficient to affect the whole body after percutaneous absorption. Contains no pharmacologically active ingredients. According to another embodiment, the patch includes a polar compound such as DMF, but does not include other antiviral agents such as acyclovir or allyldon.
Accordingly, the present invention provides a skin patch comprising an effective amount of a polar compound such as DMF for the treatment of a viral or microbial infection (eg, HIV infection) in a human adult or infant. Furthermore, the present invention provides a skin patch comprising an effective amount of a polar compound such as DMF for the treatment of debilitating syndrome in a human adult or infant. According to an embodiment of the present invention, the patch comprises at least 0.25 g, desirably at least 0.5 g, more desirably at least 1 g, more desirably at least 5 g, for example 5-15 g of polar compound such as DMF.
In order to prevent loss due to volatilization of polar compounds, patches may be stored in sealed containers such as sealed polymer bags. If necessary, each patch may be sealed separately for convenience during use. If necessary, the patch may be stored refrigerated at, for example, about 4 ° C. before use to prevent loss due to volatilization of polar compounds. Desirably, the patch may be prepared 24 hours prior to use and stored in a sealed container at 4 ° C. However, the patch is stable for more than a week when stored in a sealed container at 4 ° C. Before applying the patch, wash the skin at the application site with mild soap and water, rinse to wash away the rest of the soap, dry well, and KY^TMIt is desirable to humidify with a suitable skin lubricant and wetting agent such as jelly. Next, the patch is taken out from the package and attached so that the permeable membrane is in close contact with the prepared skin surface. The patch may be fixed with an applicator. After a predetermined treatment time, the patch is removed. After removing the patch, wash the treated area thoroughly with mild soap and water and wash away any remaining polar compounds.
The compositions of the present invention may be administered at intervals as needed, for example, once every 2-3 weeks, once a week, twice or three times, once every two days, or daily. Desirably, the composition of the present invention is administered such that the maximum plasma concentration of an active ingredient such as DMF in the composition is about 2 to 200 mg / L, more preferably about 100 to 200 mg / L, more preferably 150 mg / L. To do. A maximum plasma concentration of DMF of 100 to 150 mg / L or 150 to 200 mg / L is particularly desirable. As used herein, “ppm” means parts per million by weight and is substantially equal to mg / L.
In transdermal administration of a polar compound, the absorption rate from the skin of the subject is measured. The liquid DMF treated on human skin is about 9.4 mg / cm²Absorbed at a constant rate per hour (see Mraz & Nohova, 1992, Occup. Env. Health 64: 85-92). Therefore, the target absorption rate can be obtained by controlling the surface area of the skin on which the drug is treated according to the area of each patch and the number of patches to be applied to the skin. For example, two patches 9 cm in diameter impregnated with a polar compound have a total area of 127 cm²When applied to the skin, DMF provides an absorption rate of about 1.2 g / hour. It is particularly desirable that the initial dose of DMF be about 15 mg / kg.
In one embodiment of the present invention, when DMF is treated by applying 2 patches of 9 cm in diameter to a patient weighing about 72 kg for 1 hour, the initial amount of DMF absorbed is about 1.2 g, which is about 16.7 mg / equivalent to kg. Depending on the weight of the patient to be treated, the number of patches is increased or decreased, and the application time is increased or decreased. This initial treatment dose is administered repeatedly at predetermined intervals, preferably once a week, as described above. Desirably, enzyme concentrations such as serum or plasma aspartate transferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (γGT) and alkyl phosphatase, and protein concentrations such as albumin over at least 72 hours after administration of DMF, Alternatively, the patient is monitored for toxic symptoms such as liver toxicity by measuring the concentration of a substance such as conjugated or unconjugated bilirubin. AST and ALT concentrations in serum or plasma are preferably within 5 times the upper limit of the normal range of the laboratory or the relevant population, more preferably within 3 times of the upper limit of the normal value, especially exceeding normal It is desirable not to exceed or exceed the pretreatment concentration. The dose of DMF may be escalated by sequentially increasing the patch application time. According to the embodiment of the present invention, the patch application time is increased to 2 hours, 4 hours, 6 hours, and the like. According to another embodiment, the patch application time is sequentially doubled. When escalating the application time, it is desirable to examine the patient in advance to detect toxic symptoms. If necessary, escalate application time at weekly intervals. In this way, until the calculated dose reaches about 150 mg / kg / dose, or until the desired maximum plasma concentration, eg 100-150 or 150-200 mg / L, is obtained, or the application time is about 6 hours or Escalate the dose until approximately 8 hours. Care should be taken when increasing the dose to 240 mg / kg / dose or more.
6). Example: Treatment of HIV infection by transdermal administration of N, N'-dimethylformamide (DMF)
Dimethylformamide was treated in HIV-1 infected patients by applying a skin patch impregnated with dimethylformamide (DMF) gel to the patient's body. As a liver booster, N-acetyl-cysteine-glutathione and / or essential phospholipids were administered to patients at a dose of 250-300 mg / day (oral administration or intravenous injection). Alternatively or additionally, glutamine may be administered to the patient as a liver booster.
Two skin patches were applied to different parts of the patient's body, for example the forearm. Each skin patch contains about 7.06 g of gel containing DMF (92.5% m / m) and colloidal silicon dioxide (7.5% m / m). The gel serves to prevent leakage of liquid DMF from the patch. Since DMF evaporates rapidly, the patch was prepared about 12 hours before use. The target value of the patient's blood DMF concentration was set to 100 ppm. In order to obtain a blood concentration of 100 ppm in a patient weighing about 60 kg, it is necessary to apply about 14 g for 12 hours. The surface area required to absorb this amount, calculated based on the Marz & Nohova test, is approximately 127.2 cm.²It is. In order to obtain a blood concentration of 100 ppm, it is necessary to absorb about 1.272 g of DMF per hour. Therefore, approximately 7.064 g of DMF is added to each sticker to deliver a predetermined amount of 6.36 cm.²Required surface area (each sticker). The absorption rate of DMF is 9.4 mg / cm.²/ Hour. This treatment should theoretically provide 125-135 ppm, but 100 ppm was obtained by volatilization of DMF. Absorption capacity depends on factors such as skin type and skin thickness and varies from patient to patient. In order to obtain a predetermined DMF concentration, the plasma DMF concentration was measured for each patient and the treatment was adjusted according to the DMF concentration of each patient. FIG. 1 shows the plasma DMF concentrations of 4 patients to whom 2 DMF patches were applied for 8 hours. FIG. 2 shows plasma DMF concentrations of 3 patients to whom 2 DMF patches were applied for 6 hours.
Each sticker was thus filled with about 7.064 g of gel containing DMF and silicon dioxide. Each patch was applied for 12 hours once a week for 12 weeks or twice a week for 6 weeks.
In some patients' blood tests, CD3 T-cell increase from 350 to 1000 and PCR (polymerase chain reaction) (viral load) from 120,000 to 500 / ml within 3 weeks after only 3 treatments A drastic decrease was observed. A series of quantitative values by PCR of HIV-1 viral load in patients before treatment and after 3 treatments with 12 DMF skin patches applied for 12 hours is shown in FIG. PCR tests were performed using a Roche Amplifier HIV monitor. The detection limit of virus load was 500 / ml.
Some patients undergoing treatment experienced severe acne or rubella symptoms prior to treatment. When DMF was treated so that the patient's blood DMF concentration was 50-100 ppm, the rubella symptoms and severe acne disappeared within 7 days.
Prior to treatment with dimethylformamide, patients were subjected to an extensive clinical and psychological baseline assessment. Baseline data were obtained by biochemical and hematological assessment of patients. A detailed virological serological (HIV-1) study was also performed to count the total virus count in the patient. These tests were performed once a week or at each treatment.
The patient's blood DMF concentration was taken every hour during the treatment period. A venous catheter was inserted every morning to collect a blood sample, and saline was infused at a rate of 20 ml / hour and remained inserted while preventing clogging. The active metabolite AMCC derived from DMF was measured daily (eg, a 4 hour urine sample was taken). Subsequent DMF treatment was adjusted based on changes in absorption variables, and complete hematological and biochemical profiles were measured daily to detect changes in liver function. A complete clinical and psychological evaluation was also performed.
Viral serological tests were performed daily to determine total body virus counts and to follow improvement in patient immune status (CD4 T-helper cells) and prognostic factors. Serological testing was based on p24 antigen and quantitative PCR, or possibly other methods. Measurements of CD4 count and β-2-macroglobulin were also taken weekly, especially to follow improvement in the patient's immune status and prognosis. All clinical and laboratory data was entered into a centralized data system to respond quickly to adverse changes, maximize clinical effectiveness, and adjust application time to minimize side effects.
This test includes the following items:
a) Serum: Na, K, Cl, CO₂, Urea, creatinine, Ca, Mg, inorganic phosphorus, total and conjugated bilirubin
b) Hematological examination: hemoglobin, red blood cell count, hematocrit, MCV, MCH, MCHC, RDW
c) Serum protein electrophoresis: total protein, albumin, total globulin, α-globulin, α2-globulin, β-globulin, γ-globulin
d) Leukocyte analysis: leukocyte percentage, absolute neutrophils, lymphocytes, monocytes, eosinophils, and basophil counts
e) Liver enzymes: alkaline phosphatase, γ-GT, ALT (SGPT), AST (SGOT), LDH
f) Other: Cell marker, PCR, β2-macroglobulin, p24 antigen, C-reactive protein, CK-MR concentration
g) Analysis of blood DMF concentration
h) Analysis of AMCC concentration in urine
DMF acts as at least one inhibitor of reverse transcriptase and protease as described above. In an in vitro test, DMF appears to dissolve virus particles, such as capsids, due to its properties as a solvent.
7). Example: Treatment of HIV infection by transdermal administration of N, N'-dimethylformamide (DMF)
A pilot study was conducted to evaluate the effects of DMF administered transdermally to HIV-infected patients. Informed consent was obtained from each patient. Seropositive status was confirmed by Western blot analysis using a commercially available kit for detecting p24 antibody (Abbott Diagnostics), and the presence or absence of HIV-1 was recorded by quantitative PCR using a commercially available kit (Roche Amplifier).
DMF (Sigma-Aldrich) purchased and DMF in plasma samples were measured using a Varian 9600 gas chromatograph, an OV 351 column, a carbowax-PEG capillary column, a mass spectrometer / gas chromatography (GC / GC) using a Finnegan Mat ITS40 ion trap detector. MS). The operating parameters were set as follows. GC temperature rising program: temperature gradient of 1 minute at 60 ° C, then 20 minutes at 9.4 ° C / minute.
MS ionization method: EI method. Mass range: 40-80 mass units, 1 scan / second. Peak threshold: 3 counts / second. Background mass: 69 mass units. As an internal standard, a stock solution of dimethylacetamide was used. All samples were extracted with an organic solvent containing an internal standard, and left to stand for 30 minutes in a refrigerator for precipitation. It was then centrifuged at 3000g for 5 minutes and transferred to a GC vial for injection. The DMF peak retention time for the internal standard was 3.26 minutes, and the correlation coefficient of the calibration curve was 0.98. The quantification of DMF was linear up to a concentration of 100 mg / L and the detection limit was 0.5 mg / L with a signal to background ratio of 3: 1.
A 9 cm diameter skin patch was used within 12 hours after preparation. Each patch consists of a high density polyethylene backing (0.245 g) and Teflon for skin contact^TMIt contained a permeable membrane (pore size 0.2 μm, 0.268 g) and contained 0.573 g of silicon dioxide impregnated with 7.067 g of DMF between the backing and the permeable membrane. The patch was confirmed to be free from leakage by visual inspection, and the difference from the total weight of 8.153 g was confirmed to be within 10% using an analytical balance. Apply the patch to the skin of the forearm, Elastoplast^TMFixed with bandages. For the first treatment, the predicted skin transfer rate of 9.4 mg / cm²One or two patches were used per hour / time and patient weight.
Blood and urine were collected every 2 hours using graded doses of DMF to determine the peak plasma DMF concentration. In the course of increasing the dose until the plasma DMF concentration reached a peak of 100-120 ppm, the patient was clinically followed for adverse side effects and placed under extensive biochemical examination. Once the correct dose was established, DMF was administered transdermally once a week. As an initial evaluation, the following items were measured daily.
a) Signs of survival and body weight
b) Clinical Checklist and Karnofsky Rating
c) Complete blood count and sedimentation
d) Serum urea, creatinine, glucose, Na, K, ALT, AST, alkaline phosphatase, and total bilirubin
e) CD4⁺And CD8⁺Coulter counter analysis of numbers and CD4 / CD8 ratio
f) Evaluation of HIV-1 levels by PCR (Roche Amplifier) and analysis of p24 antibody (Abbott)
g) Urinalysis (Dipstix)
At weekly outpatients, the adverse effects of the patients were assessed, and almost all of these tests were repeated, and blood and urine were collected for analysis of DMF and its metabolites.
Patient 1 (ADF) was in good health at the start of the study and complained mainly of limb pain and insomnia. Two DMF patches were administered once a week with an average application time of 8 hours. The weekly average DMF dose was 6.11 g, and the peak plasma DMF concentration obtained was 75 mg / L on average. 9 weeks later, patient's CD4⁺The number of T cells increased from 140 to 640 cells / μL, and the viral load measured by PCR decreased from 250,000 to 50,000 copies / mL. After 10 weeks, the body weight increased from 81.9 to 96.0 kg, the patient was in good clinical condition and no longer complained of limb pain.
Patient 2 (AM) complained of loss of power, insomnia, and pain in the limbs when the test was started, and herpes was found in the oral cavity. One DMF patch was administered once a week with an average application time of 8 hours. The weekly average DMF dose was 7.12 g, and the peak plasma DMF concentration obtained was 125 mg / L on average. 9 weeks later, patient's CD4⁺The number of T cells increased from 460 to 720 cells / μL, and the viral load measured by PCR decreased from 29,000 to 13,000 copies / mL. Patient weight increased from 58.4 to 63.0 kg. The patient's herpes disappeared and the pain in the limbs disappeared, which seemed clinically good.
Patient 3 (SM) was clinically apparently suffering from AIDS at the start of the study and complained of dyspnea. Two DMF patches were administered once a week with an average application time of 8 hours. The weekly average DMF dose was 8.97 g, and the peak plasma DMF concentration obtained was 121 mg / L on average. 7 weeks later, patient's CD4⁺The number of T cells increased from 39 to 138 cells / μL, the viral load measured by PCR decreased from 222,000 to 160,000 copies / mL, and the patient's body weight increased from 74.2 to 100 kg. The patient's appetite was restored, dyspnea disappeared, the patient was clinically good, and exercise started again.
Patient 4 (EM) had secondary infection (rubella), anemia, diarrhea and acne at the start of the study. Two DMF patches were administered once a week with an average application time of 8 hours. The weekly average weekly DMF dose was 7.33 g, and the peak plasma DMF concentration obtained was 90 mg / L on average. 18 weeks later, patient's CD4⁺T cell count increased from 249 to 450 cells / μL, viral load measured by PCR decreased from 13,000 to 4,000 copies / mL, and patient weight increased from 81.5 to 90.4 kg . The patient was clinically good and there were no medical complaints.
Patient 5 (SV) was considering selling business assets due to loss of appetite, forgetfulness, abdominal pain, and severe fatigue when the trial was started. Two DMF patches were administered once a week with an average application time of 6 hours. The weekly average weekly DMF dose was 3.75 g, and the peak plasma DMF concentration obtained was 67 mg / L on average. After 5 weeks, the patient's CD4⁺T cell count increased from 354 to 396 cells / μL, viral load measured by PCR decreased from 156,000 to 13,000 copies / mL, and patient weight increased from 56.0 to 58.0 kg. . The patient was clinically good and he bought his own business and started doing his own business.
Patient 6 (VV) complained of secondary infection (rubella), ataxia, numbness of the left arm and left face when the study was started. Two DMF patches were administered once a week with an average application time of 8 hours. The weekly average weekly DMF dose was 8.25 g, and the peak plasma DM concentration obtained was 110 mg / L on average. After 19 weeks, the patient's CD4⁺T cell count increased from 260 to 450 cells / μL, viral load measured by PCR decreased from 120,000 to 24,000 copies / mL, and patient weight increased from 75.4 to 84.6 kg. . The secondary infection disappeared and the patient was clinically good.
Patient 7 (AJF) was in very poor health when he started the study. Patient's CD4⁺The number of T cells was 29 cells / μL, and the viral load measured by PCR was 1,156,000 copies / mL. One DMF patch was administered with an average application time of 4 hours. The weekly average weekly DMF dose was 4.60 g, and the peak plasma DM concentration obtained was 100 mg / L on average. After the first treatment, the patient's CD4⁺The T cell count was reduced to 14 cells / μL. The treatment was continued for 5 days every day and thereafter once a week. 9 weeks later, patient's CD4⁺T cell count increased to 35 cells / μL, viral load measured by PCR decreased to 9,000 copies / mL, and patient weight increased from 46.5 kg (at the start of DMF treatment) to 49.0 kg. . The patient was well and returned to regular work.
Patient 8 (MS) had severe herpes on the lumbar region and perineum when starting the study. Two DMF patches were administered once a week with an average application time of 8 hours. The average weekly DMF dose was 6.24 g, and the peak plasma DMF concentration obtained was 130 mg / L on average. After 8 weeks, the patient's CD4⁺The number of T cells increased from 200 to 240 cells / μL and the viral load measured by PCR decreased from 1,200,000 to 250,000 copies / mL. The patient's weight increased from 48.1 to 52.2 kg and the rubella lesion disappeared completely.
Two patients were excluded from the study. One was alcohol abuse and one was infected with hepatitis B virus.
Most patients experienced mild local skin irritation at the site of application after patch removal. Apical papules were observed on the skin of the application site, which seems to be due to excessive moisturization under the patch. In one case, mild blistering was observed, but it disappeared within 24 hours and did not give significant discomfort to the patient. Most patients were usually mild 3 days after treatment, experienced transient nausea and gradually decreased as the study progressed, while one patient complained of moderate transient nausea. Four patients had a transient increase in liver enzymes but did not exceed the upper limit of three times the normal value, and in most cases recovered to pre-treatment values by the next dose of DMF. . In most cases, elevated liver enzymes were associated with at least one factor unrelated to administration (drinking, hepatitis, history of anti-HIV treatment with other drugs).
As a result, clinical improvement was observed in most patients after 2-3 weeks of treatment. As shown in FIG. 4, when evaluated according to Karnofsky performance scores, improvements in general condition were observed in any patient. In this method, the general state of the patient was evaluated by the score as follows. 100 = normal (no symptom complaints), 90 = normal activity (symptoms of the disease are very slight), 80 = normal activity is possible with effort, 70 = self care is possible ( Normal activity or work to move the body is difficult), 60 = sometimes need assistance, but most of the time you can take care of yourself, 50 = require some assistance, need frequent medical care, 40 = Incompetent, need special medical care, 30 = severe incompetence, need hospitalization but not deadly, 20 = severe sick, need hospitalization and frequent care 10 = dead, drowning rapidly 0 = death (see Kanofsky et al., 1984, Cancer 1: 634-656). The improvement in neurological symptoms and herpes virus infection was significant. Treatment of secondary infection with another antimicrobial therapy was rarely necessary. Within 14 days after DMF treatment, general fatigue and significant improvement in appetite were observed. All patients showed weight gain. Viral load and CD4⁺There was a good correlation between clinical improvement and disease state when assessed by T cell count. The relative viral load as measured by PCR in 5 out of 8 patients fit the Gompertz curve, and this analysis showed an 88.8% reduction in viral load measured by PCR 42 days after DMF treatment. Relative CD4 in 7 out of 8 patients⁺The T cell count fits the Gompertz curve and in this analysis the CD4 was 42 days after DMF treatment.⁺An increase of 73.4% was observed in the number of T cells.
The illustrated embodiments are not intended to limit the scope of the present invention, but only to illustrate certain aspects of the present invention. In fact, it will be apparent to those skilled in the art that various modifications besides those shown and described herein are possible from the foregoing description and accompanying drawings. Such modifications are considered to be within the scope of the present invention.
Publications cited herein are incorporated by reference in their entirety.

Claims (8)

A drug delivery device for transdermal administration of a therapeutic composition for the treatment of patients suffering from wasting syndrome associated with HIV infection,
The device
To the back,
A permeable membrane suitable for placement on the skin of an animal treatment site;
Having an absorbent disposed between the backing and the permeable membrane;
The therapeutic composition contains an effective amount of N, N′-dimethylformamide (DMF) as a therapeutic agent for the treatment of wasting syndrome associated with HIV infection ,
The absorbent material adsorbs the therapeutic composition on its surface;
The drug supply apparatus is adapted for use in close contact with the skin of a patient for the purpose of treating wasting syndrome associated with HIV infection . The therapeutic composition contains at least 1 g of DMF as a therapeutic agent for treating wasting syndrome associated with HIV infection. Drug supply device. The therapeutic composition contains at least 5 g of DMF as a therapeutic agent for treating wasting syndrome associated with HIV infection. Drug supply device. The said therapeutic composition contains 5-15g of DMF as a therapeutic agent aiming at the treatment of the wasting syndrome related to HIV infection. Drug supply device. The medicament according to any one of claims 1 to 4, characterized in that the therapeutic composition further comprises one or more other medicaments effective in the treatment of HIV infection. Feeding device. The drug supply device according to any one of claims 1 to 4, wherein there is no other drug effective for treating HIV infection other than DMF. 5. In addition to DMF, there is no other drug capable of systemic absorption through the skin and effective in the treatment of HIV infection. Drug supply device. The absorbent is colloidal silicon dioxide;
The drug supply according to any one of claims 1 to 7, wherein the permeable membrane is a Teflon ^TM membrane having pores having a pore diameter of about 0.1 µm to about 0.5 µm. apparatus.

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