CN1512890A - HCG preparations - Google Patents

Abstract

The invention relates to a pharmaceutical composition comprising a biologically active protein or a peptide formulated in water-in-oil emulsion with or without muramyl peptide. More specifically it relates to a preparation of human chorionic gonadotropin (hCG) and related hormones. Also provides are methods of making the composition; methods of using the same against viral infections, immune disorders, and cancer.

Description

HCG preparations

technical field

In general, the present invention relates to pharmaceutical preparations of biologically active water-soluble proteins or polypeptides, such as hCG hormone, which can be used to treat different diseases. Especially preferred diseases to be treated by the compositions of the present invention are immune and malignant diseases caused by viruses. More specifically, diseases caused by viruses in humans, such as the human immunodeficiency virus (HIV), which causes Acquired Immunodeficiency Syndrome (AIDS), and related cancers are contemplated.

Background knowledge and discussion of relevant technologies

Human chorionic gonadotropin (hCG) belongs to the glycoprotein hormone family that includes luteinizing hormone (luteinizing hormone, LH), follicle-stimulating hormone (FSH) and thyroid-stimulating hormone (TSH). These hormones are each composed of two distinct non-covalently associated subunits, an alpha subunit and a beta subunit. These hormones share a common alpha subunit, while the beta subunits are unique and differ in length and amino acid sequence. The most similar hormones are hCG and LH, which are 85% identical except for an amino acid sequence at the C-terminus of hCG. HCG and LH act on the same receptor. According to the traditional view, hCG and related hormones play a role in normal human physiology. For example hCG is well established as a progestogen that plays an important role in reproductive physiology during pregnancy. An extensive background on hCG is provided in a review written by the present inventors (see Hernan F. Acevedo, "Human chorionic gonadotropin: the hormone of life and death, a review" (Human chorionic gonadotropin (hCG): hormone of life and death, a review) is hereby incorporated by reference).

Recently, it has been suggested that the hCG hormone may also be used in the treatment of HIV/AIDS and cancer. See eg US Patent Nos. 5700781; 5811390; 5851997; 5997871; 5877148 and 5677275 or original works by Bourinbaiar AS, Nagorny R. The effect of human chorionic gonadotropin (hCG) on reverse transcriptase activity in HIV-1 affects lymphocytes and monocytes. FEMS Microbiol Lett. 1 September 1992, 75(1):27-30, and original work by Bourinbaiar AS, Nagorny R. Inhibitory effect of human chorionic gonadotropin (hCG) on HIV-1 transmission from lymphocytes to vegetative cells. FEBS Lett, 1992 Aug 31;309(1):82-4, the contents of which are hereby incorporated by reference. However, some investigators have suggested that contaminating agents found in some commercially available hCG preparations are responsible for the anti-HIV and anticancer activity, refuting the notion that hCG has antiviral and anticancer activity. See for example Lee-Huangs, Huang PL, Sun Y, Huang PL, Kuang HF, Blithe DL, Chen HC. Lysozyme and RNase as anti-HIV components of human chorionic gonadotropin β-core preparations. Proc Natl Acad Sci USA. March 16, 1999, 96(6): 2678-81; Sairam MR, Antakly T. Debunking hCG. Nat Biotechnol, November 1997, (12): 1228, Albini A, Paglieri I , Orengo G, Carlone S, Aluigi MG, DeMarchi R, Matteucci C, Mantovani A, Carozzi F, Donini S, Benelli R. Human chorionic gonadotropin beta-core fragments inhibit Kaposi's sarcoma-derived cells and de novo immortalization Growth of the Kaposi's sarcoma cell line. AIDS. 1997 May;11(6):713-21; Lunardi-Iskandar Y, Bryant JL, Blattner WA, Hung CL, Flamand L, Gill P, Hermans P, Birken S, Gallo RC. From early pregnancy Effects of urine factors on HIV-1, SIV and related diseases in women. Nat Med. 1998 Apr, 4(4):428-34; Sipsas NV, Aroni K, Tsavaris N, Mavragani K, Paikos S, Kordossis T. AIDS-associated cutaneous Kaposi's sarcoma: administration of human chorionic gonadotropin Treatment failure. 1999 Feb;11(1):78-9; Masood R, McGarvey ME, Zheng T, Cai J, Arora N, Smith DL, Sloane N, Gill PS. Antitumor urinary proteins in vivo and in vitro Both can inhibit Kaposi's sarcoma and angiogenesis. Blood, 1999 Feb 1, 93(3):1038-44; Griffiths SJ, Adams DJ, Talbot SJ Ribonuclease inhibition of Kaposi's sarcoma. Nature, December 11, 1997, 390(6660): 568; Darzynkiewicz Z.butler can be used to search for ingredients that kill Kaposi's sarcoma in human chorionic gonadotropin products. J Natl Cancer Inst. 1999 Jan 20;91(2):104-6 and Noonan D, Albini A. Anti-KS activity remains a mystery. Nat Med. 1998 Jul;4(7):748; the abstract of the above article is hereby incorporated by reference. Because of the confounding results, some authors have proposed that urine of pregnant women and commercially available clinical-grade crude hCG contain different factors with anti-Kaposi's sarcoma and anti-HIV activity. Factors such as eosinophil-derived neurotoxin (EDN), antineoplastic urinary protein (ANUP), inhibin, activin A, and angiostatin were found in urine. Furthermore, some authors openly caution that hCG may have the opposite effect, that it may promote carcinogenesis, such teachings effectively depart from the usefulness of hCG as an anticancer and antiviral agent. See, for example, Simonart et al (Simonart T, Hermans P, Van Vooren JP, Meuris S. Paradoxical pro-Kaposi's sarcoma activity of preparation of human chorionic gonadotropin preparations) gonadotropin). Blood, 1999 Jul 1;94(1):367-7).

Although there is still considerable debate in the state of the art about whether hCG or a certain contaminating agent has antiviral and anticancer activity, from a practical point of view, it is inconvenient to use hormones or contaminating agents in commercially available hCG preparations of. Like many other water-soluble glycoprotein hormones, hCG can be rapidly metabolized in the body, so its half-life is relatively short. This necessitates frequent hormone injections or increased hCG doses, both of which are impractical and expensive. See U.S. Patent No. 5,700,781 "Method for treating Kaposi's sarcoma and HIV infections" to Harn, incorporated herein by reference.

Modified forms of hCG delivery, so-called "slow-release" or "sustained-release" forms of hCG were proposed early on, but no one has successfully implemented them because there are no specific assurance guidelines for these particular forms of the hormone. For example, see US Patent No. 5851997 "Use of human chorionic gonadotropin as an immune-potentiating antiviral agent" issued to Ham. In this patent, Harris lists different forms of slow release of hCG. In particular, Harris teaches a sustained release form of hCG for use as a transdermal hCG patch, a successor to the popular DURAGESIC ^™ fentaryl patch, which enables the transdermal delivery of hCG-like proteins This can be done by means of iontophoresis or electroosmosis, ie under the influence of an electric field. Another sustained-release form of hCG that Harris has in mind is an implantable hCG delivery system. Implanted with a typical device of this category, NORPLANT ^™ Levonorgestrol, the system carries out the passive delivery of hCG through a non-biodegradable, rate-limiting membrane element, for example composed of a hydrogel or a microporous polymer. Another type of hCG implantation that Harris contemplates combines hCG administration with pumping functions. This pumping action is either osmotically driven or patient activated. Thus, Harris teaches alternative modes of hCG administration. However, the modes of delivery considered are all using some specific sustained release drug delivery devices, namely transdermal patches and different types of implants or pumps. No other form of hCG delivery is known to be a reliable and practical mode of administration.

Muramyl peptide alone was reported by these inventors and others to inhibit retroviral replication (Acevedo HF, Raikow RB, Acevedo HO, Delgado TF, Pardo M. Protection against Prevention of oncogenic viral infectious in mice with CGP 11637, asynthetic muramyl dipeptide analog, Antimicrob Agents Chemother, November 1985, 28(5): 589-96; Lazdins JK, Woods-Cook K ., Walker M, AlteriE. Lipophilic muramyl peptide MTP-PE is a potent inhibitor of HIV replication in macrophages (Thelipophilic muramyl peptide MTP-PE is a potent inhibitor of HIV replication in macrophages) AIDS Res Hum Retroviruses, 1990 Oct, 6(10):1157-61; Masihi KN, Lange W, Rohde-Schulz B, Chedid L, Muramyl dipeptide inhibits replication of human immunodeficiency virus in vitro vitro). AIDS Res Hum Retroviruses, March 1990, 6(3):393-9.

However, the combined use of hCG and muramyl peptides is contrary to current thinking in the art, since muramyl peptides are primarily used as vaccine adjuvants to enhance the immune response to hCG, the antigen in vaccine preparations (see e.g. Patent No. 5840313 or 5876724), thus, this composition is effective in inactivating hCG or even aggravating the disease process. The prospect that clinical use of muramyl peptides could exacerbate HIV is particularly worrisome, based on observations by others that certain muramyl peptides actually enhance HIV replication (Schreck R, Bevec D, Duror P, Baeuerle PA, Chedid L, Bahr GM. Selection of a muramylpeptide based on its lack of activation of nuclear-kappa B as a potential adjuvant for AIDS vaccines AIDS vaccines), Clin Exp Immunol, 1992 Nov, 90(2):188-93, Masihi KN, Lange W, Rohde-Schulz B. Human immunodeficiency virus infection of promonocytes exacerbated by bacterial immunomodulators (Exacerbation of humanimmunodeficiency virus infection in promonocytic cells by bacterialimmunomodulators) J Acquir Immune Defic Syndr, 1990; 3(3): 200-5). So far, whether MDP isolated from natural sources or artificially synthesized, when administered to mammals, it is accompanied by significant toxicity. This toxicity significantly limits the clinical use of MDP. Occasionally, though, muramyl peptides are thought to be useful when administered in combination with biologically active proteins. For example, US Patent No. 5,932,208 discloses compositions in which muramyl peptides are used in combination with certain cytokines, but the authors do not teach the combination with hCG.

However, in the prior art, combinations of hCG variants and muramyl peptides are known primarily for use as fertility or cancer vaccines. These vaccines contain only the hCG beta chain or the C-terminal peptide of the hCG beta chain, and not all dimeric hCG (see U.S. Pat. , 4855285, 4791062, 4767842 and 4762913). The preference for hCG beta chain or its peptides is mainly due to the consideration that immunization with dimers or whole hCG will cause undesired cross-reactivity with some related glycoprotein hormones such as LH, FSH and TSH , with subsequent deleterious consequences for the host. To date, no prior art references exist regarding the combined use of hCG dimers and muramyl peptides.

Contrary to the conventional wisdom prevailing in the prior art, the present inventors have surprisingly found that the combined use of monolithic or dimeric hCG molecules and muramyl peptides synergistically enhances anti-HIV and anti-cancer activity in vivo without Harmful effects on the host. Also, it was surprisingly found that hCG formulated in oil-in-water emulsion with or without muramyl peptide had the same potent clinical effect.

Contents of the invention

It is therefore an object of the present invention to provide a new composition which overcomes the above mentioned and other disadvantages in the art. The present invention first successfully reduces the application practice of specially formulated water-soluble hormones in the treatment of viral diseases and cancers. In view of these and other considerations, the present inventors have discovered that administration of hCG and muramyl peptides has a better clinical effect or response than administration of unmodified forms of hCG currently available on the market. It is also contemplated that HCG is formulated in an oil-in-water emulsion with or without muramyl peptide. Other formulations such as encapsulated liposomal delivery forms are equally suitable. Accordingly, the present invention contemplates a composition comprising a novel therapeutic form of dimeric hCG.

Another object of the present invention is to provide a process for the preparation of the composition, which also overcomes the drawbacks in the art.

The present invention also contemplates methods of administering to a subject an amount of hCG preparations that are clinically more effective in treating or preventing viral infections that the subject has or will have of.

According to another aspect of the present invention, some methods for treating cancer in a test animal such as a human are also provided, wherein a certain dose of the instant composition is administered to the test subject, and the dose is effective for eliminating or preventing the cancer in Growth in the animals was efficient.

Some preferred uses contemplated by the inventors are in diseases such as AIDS, Kaposi's sarcoma (including endemic and HIV-related types), multiple myeloma, lymphoma, melanoma and other forms of cancer and leukemia. treat.

Without implying any limitation, these pharmaceutical compositions may advantageously be prepared in the form of solutions which may be administered parenterally, especially subcutaneously, intramuscularly, intravenously or by perfusion. The composition of the invention is equally effective and advantageous when administered orally alone or in the form of a galenic. Encapsulation of these compositions in galenic form, eg in capsule form or in the form of spheroids or liposomes, enables them to cross the gastric barrier.

Best Mode for Carrying Out the Invention

The present invention is based on the discovery that although muramyl dipeptides (MDPs) are commonly used as components of vaccine preparations to induce immunity to vaccine antigenic clusters, these muramyl peptide compounds actually act synergistically with hCG activity in vivo , rather than antagonizing the activity of hCG. Notwithstanding what is taught in the art above, the combination of muramyl peptide compounds and hCG is useful in the treatment, prevention and management of HIV infection and other life-threatening conditions, such as cancer.

The term "continuous delivery device" as used hereinafter refers to specific devices such as transdermal patches, subcutaneous implants and medicated pumps.

The term "slow release formulation" as used hereinafter refers to a drug delivery form rather than a sustained delivery device, including hCG formulations not mentioned in the art in relation to hCG formulations.

The term "adjuvant" defines a substance that is incorporated into or injected with an antigen. Adjuvants non-specifically enhance subsequent immune responses to antigens. A major purpose of using adjuvants for immunotherapy is to achieve longer-lasting high-level humoral or cell-mediated immunity by administering smaller doses of low-level antigen than the equivalent amount of aqueous antigen. Adjuvants are often used in vaccine preparation in combination with non-living agents (in place of living microorganisms). Adjuvants are also effective in enhancing the immune response to tumor cells with low or non-immunogenicity and to cells infected with intracellular material that is already present in the body and cannot be adequately responded to by a naturally induced immune response Prevent.

The term "emulsifier" as used hereinafter means a nonionic surface-active compound derived from alkylene oxides and/or hexahydric alcohols and/or higher natural fatty acids such as esters or ester-ethers.

The term "Complete Freund's Adjuvant" (CFA) refers to a potent immunostimulant that has been used successfully on an experimental basis with many antigens. CFAs include mineral oil, emulsifiers/stabilizers such as sorbitan A, and killer mycobacteria such as Mycobacterium tuberculosis. The aqueous antigen/protein solution and these ingredients are mixed together to form a water-in-oil emulsion. However, CFA can cause serious side effects, including pain, abscess formation, and fever, which prevent its use in human or veterinary vaccines. Side effects are primarily produced by the patient's response to the mycobacterial component of CFA.

"Incomplete Freund's Adjuvant" (IFA) is similar to CFA except that it has no bacterial component. Although not approved for use in the United States, IFA has been used in several types of vaccines in other countries. IFA has been used successfully in humans with influenza and poliovirus vaccines and several other animal vaccines including rabies, distemper, and foot-and-mouth disease vaccines. Experiments have shown that both the oil and the emulsifier used in IFA can cause tumors in mice, which means that choosing an alternative adjuvant is a better choice for use in humans.

Muramyl dipeptide (MDP) represents the smallest unit in the mycobacterial cell wall complex, and its adjuvant activity can be observed with CFA. A number of synthetic MDP analogs have been produced which exhibit a wider range of adjuvant potential and side effects. Three analogues are particularly useful as vaccine adjuvants, threonyl derivatives of MDP, n-butyl derivatives of MDP and lipophilic derivatives of muramyl tripeptide (see US Patent No. 5709879). These compounds potently stimulate humoral and cell-mediated immunity while exhibiting only low levels of toxicity. The muramyl peptide has a phospholipid tail, which allows the hydrophobic portion of the molecule to associate with the lipid environment, while the muramyl peptide portion binds to the aqueous environment. Therefore, MTP-PE itself can be used as an emulsifying agent to produce a stable oil-in-water emulsion.

The term "muramoyl peptide" has a clear meaning for those skilled in the art. It especially refers to a compound containing one or more sugar residues, at least one sugar residue, usually a muramic acid residue, replaced by at least one or more (usually 2 or more) amino acids residue substitution. The muramyl peptide compounds are peptidoglycans, which enhance the antigenic response of mammalian cells, and they are the prototype of muramyl dipeptide (MDP) or its analogs or derivatives.

Many previously disclosed muramyl peptide compounds play a role in the treatment or prevention of progressive leukemia and septic shock, and possess immunopotentiating antibacterial activity. However, muramyl peptide molecules are only effective in immunocompetent hosts. For representative muramyl peptides see US Patent Nos. 5,506,204 and 5,534,492, which are incorporated herein by reference.

A variety of prototypical analogues of muramyl dipeptides are known, some of which have been proposed as therapeutic means for restoration of immune function or non-specific stimulation of the immune system. These analogs, and the prototype MDP itself, are collectively referred to as "muramoyl peptides".

In a first aspect, the present invention provides a composition of a muramyl peptide compound and a water-soluble bioactive protein such as hCG.

Without being limited to hCG, other therapeutic agents are also considered, including but not limited to insulin, glucagon, calcitonin, atrial peptide, secretin, cholecystokinin, thyrotropin-releasing thymopentin, corticotropin , growth hormone releasing factor, enkephalins, oxytocin, vasopressin and luteinizing hormone releasing hormone. These compositions may additionally be formulated as a matrix material selected from the group consisting of chitosan, algin, saturated polyglycolysed glyceride, glycerol palm oil methyl stearate, saturated C12 to C22 polyols Fatty acid esters, glyceryl and polyethylene glycol methyl behenate, polyethylene oxide and ammonium glycyrrhizinate, etc.

Adjuvants selected from monophosphoryl lipid A, lipid A, keyhole limpet hemocyanin, histidine tag, alum, Freund's adjuvant, β-gal, palmitic acid, saponin, lipopolysaccharide, BCG cell wall skeleton, monomycolate trehalose , dimycolate trehalose, lipid X, isoprinosine, lithosperman (A, B or C), and muramyl dipeptide (MDP) lipid crosslinks. These lipids may be saturated and or unsaturated phospholipids or glycolipids. Preferred lipids are selected from 1,2-dimyristoylphosphatidylcholine, 1,2-dipalmitoylphosphatidylcholine, 1,2-dimyristoylphosphatidylglycerol, cholesterol and combinations thereof.

Examples of solid fats suitable for the preparation of instant compositions are triglycerides composed of natural, even-numbered, unbranched fatty acids in the chain length range C10-C18, or of natural origin, saturated, even-numbered and unbranched. Microcrystalline triglycerides composed of branched fatty acids such as tricaprin, trilauroyl, trimyristoyl, tripalmitoyl and tristearin. In conclusion, any lipid component or mixture of lipid components that provides a solid phase at room temperature (25° C.) when assayed in batches is suitable for use as a lipid core.

Preferred phospholipids for use in making instant compositions are natural phospholipids such as soy lecithin, lecithin, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidic acid, sphingomyelin, diphosphatidylglycerol, phosphatidylserine, phospholipids Acylcholine, cardiolipin, etc., and synthetic phospholipids such as dimyristoylphosphatidylcholine, dimyristoylphosphatidylglycerol, distearylphosphatidylglycerol, dipalmitoylphosphatidylcholine, monophosphoryl A, diphosphoryl lipids A, etc. and hydroxylated or partially hydroxylated lecithin and phospholipids.

Non-natural surfactants and detergents can optionally be incorporated in the compositions of the present invention in amounts. The term "surfactant" or "detergent" as used herein includes a wide range of artificial molecules which form micelles in aqueous solution, containing lipophilic and hydrophilic regions. In general, emulsifiers include sorbitan esters, polyoxyethylene sorbitan mono-, di- or triesters, polyoxyethylene fatty acids, polyoxyethylene fatty acid esters and combinations thereof. Examples of non-natural surfactants include, but are not limited to, polysorbate ("Tween" or sorbitan monooleate), sodium dodecyl sulfate (SDS), polyethoxylated castor oil ( "CREMOPHOR"), NP-40 and many other synthetic molecules. In addition, several synthetic surfactants, such as dimethyl dioctadecyl ammonium bromide (DDA), certain linear polyoxypropylene-polyoxyethylene (POP-POE) block polymers (commercially available obtained under the trademark PLUPONIC), which is reported to have adjuvant activity. Among them, Poloxamer 401, Pluronic L62LF, Pluronic L101, Pluronic L64, PEG1000, Extra Jonny 1501, Extra Jonny 150R1, Extra Jonny 701, Extra Jonny 901, Extra Strong Ni 1301, Atmos 300, Tween 20, Tween 40, Tween 60, Tween 80 and Tyjonny 130R1 are particularly desirable. Emulsifiers also include Sorbitan A or Sorbitan 80 or Span 80 (so-called mannide monooleate). These adjuvants can be used in different dosages. For example in instant compositions, while the preferred range of Sorbitan A or Sorbitan 80 or Span 80 is between about 2-15% by weight, Tween 80 is in the range of 0.2-0.4% by weight. In general, the surfactant comprises less than 30%, preferably less than 25%, more preferably less than 10%, and most preferably less than 5% by weight of the total composition.

Functional equivalents of MDP, including but not limited to muramyl dipeptides or tripeptides, such as N-acetylglucosaminyl-N-acetyl-muramoyl-L-alanyl-D-isoglutamine ( GMDP), N-acetyl-D-glucosaminyl (β-1,4)-N-acetyl-muramoyl-L-alanyl-D-isoglutamine, N-acetylglucosaminyl- N-acetyl-muramoyl-L-alanyl-D-glutamate (GMDP-A), muramyl dipeptide phosphatidylethanolamine, muramyl tripeptide phosphatidylethanolamine, muramyl tripeptide phosphatidylethanolamine Ethanolamine, GGP11637 (nor-MDP), α(N-acetyl-muramoyl-L-alanyl-D-isoglutamine), β, γ-dipalmitoyl-sn-glycerol, α(N- Acetyl-muramoyl-D-alanyl-D-isoglutamine), β,γ-dipalmitoyl-sn-glycerol, α(N-acetyl-muramoyl-L-alanyl-D- isoglutamine-L-alanine), β,γ-dipalmitoyl-sn-glycerol, α(N-acetyl-muramoyl-D-alanyl-D-isoglutamine-L-propanyl amino acid), β, γ-dipalmitoyl-sn-glycerol, N-acetylmuramoyl-L-alanyl-D-isoglutamine-L-alanine-2-(1,2-di Palmitoyl-sn-glycerol-3-hydroxyphosphoryloxy)acetamide, glucosamine muramyl peptide, murametide, murabutide, muradimetide, myramistin, N-acetylmuramoyl-L-threonyl-D- Isglutamine, N-acetylmuramoyl-L-α-aminobutyryl-D-isoglutamine, 6-O-stearoyl-N-acetylmuramoyl-L-α-aminobutyl- D-isoglutamine, N-acetylmuramoyl-L-valyl-D-isoglutamine, N-acetylmuramoyl-L-alanyl-D-isoglutamine, N-acetyl -Desmethylmuramoyl-L-alanyl-D-isoglutamine, N-acetylmuramoyl-L-alanyl-D-glutamine butyl ester, N-acetylmuramoyl- L-seryl-D-isoglutamine, N-butylmuramoyl-L-α-aminobutyl-D-isoglutamine, N-acetylmuramoyl-L-threonyl-D - Isglutamine, bis(6-O-muramoyl dipeptide) O-palmitoyl propanol diacid, muramyl tripeptide phosphatidylethanolamine, N-acetylmuramoyl-L-alanyl-D -Isoglutamyl-L-alanine-2-(1,2-dipalmitoyl-sn-glycerol-3-(hydroxyphosphoryloxy))acetamide, N-acetylmuramoyl-L- Alanyl-D-glutamine butyl ester, N-acetylmuramoyl-L-alanyl-D-isoglutaminyl-L-alanine-2-1,2-dipalmitoyl- sn-glycerol-3-(hydroxyphosphoryloxy)acetamide (MTP-PE), cholesterol-MDP, beta-butylglycoside of N-acetylmuramoyl-L-alanyl-D-isoglutamine , 2-acetylamino-4,6-di-O-acetyl-2-deoxy-3-O-[(R)1-(methoxycarbonyl)ethyl]-α-D-glucopyranose, (β- Butyl MDP, MTPO-26, β-cholesterol-MDP), saponin (Taurosid I), N-acetylnor-muramoyl-L-N-methylpropionyl-D-isoglutamine octanamide, UDP-N -Acetylmuramoyl pentapeptide, L4-MDP-ONB, L-alanyl-γ-D-glutamyl-medium-diaminopimelic acid, 1,6-anhydromuramoyl dipeptide, N-acetyl Glucosaminyl-β-1, 4-N-acetylmuramoylpentapeptide-pyrophosphoryl-undedeterpene alcohol, 3-O-[acetylmuramoyl-D-isoglutaminyl]-1, 2-Dipalmitoyl-sn-glycerol, L-threonyl-MDP-GDP, L-isothreonyl-MDP-GDP, trehalose 6,6-diester, muramyl dipeptide, B30 muramyl Dipeptide and muramyl dipeptide-lysine.

It is understood that the aminoacyl residue may be selected from alanyl, valyl, leucyl, isoleucyl, α-aminobutyl, threonyl, methionyl, cysteinyl, glutamyl , isoglutamyl, glutaminyl, isoglutaminyl, aspartyl, phenylalanyl, tyrosyl, tryptophanyl, lysyl, ornithyl, arginyl, histidyl , any one of the aminoacyl moieties of aspartyl, prolyl, hydroxyprolyl, seryl and glycyl.

Additional muramyl peptide derivatives include those in which the L-alanyl residue in the muramyl peptidyl group is replaced by an L-threonyl residue. Furthermore, it is also possible to use adjuvant muramyl peptides having substituents at the 1, 4, 6 positions of the glycosyl groups, provided that they have the same advantageous effects as the preferred muramyl peptides mentioned above.无需限于上述胞壁酰肽的衍生物，那些例如已经在美国专利No4158052，4220637，4323559，4323560，4409209，4423038，4185089，4406889，4082735，4082736，4427659，4461761，4314998，4101536，4369178，5075287，5376369 , 5264431 and 5709879 (incorporated herein by reference) are equally useful in the present invention.

Other useful additives in the composition include N-cyclohexyl arginine, a mixture of N-cyclohexyl tyrosine and N-cyclohexyl leucine, N-phenylsulfonyl valine, N- A mixture of phenylsulfonylleucine, N-phenylsulfonylphenylalanine, N-phenylsulfonyllysine, and N-phenylsulfonylarginine, and N-benzoylvaline , N-benzoylleucine, N-benzoylphenylalanine, N-benzoyllysine, N-benzoylarginine and a mixture of stabilizers such as sodium 2-cyclohexylbutyrate .

Without being limited to the above ingredients, one skilled in the art can think of ovalbumin, cholera toxin, acylated amino acid and its salt, polyamino acid containing at least one acylated amino acid or its salt, a sulfonated Amino acids and their salts, or any combination of these substances. Such compositions also contain microspheres.

Polymeric matrices for forming microspheres are well known in the art. For example, semipermeable microspheres containing enzymes, hormones, vaccines and other biological products are disclosed in US Patent No. 5,643,605. Another U.S. Patent No. 5,075,109 discloses a method of promoting an immune response by administering a mixture consisting of at least two populations of bioactive agent-containing microspheres, wherein a population of microspheres is between about 1- 10 μm. US Patent No. 4,293,539 discloses controlled release formulations of active ingredients in copolymers derived from about 60-95% by weight lactic acid and about 40-4% by weight glycolic acid. US Patent No. 4919929 discloses the administration of an antigenic material having a tangible structure of a biocompatible matrix. U.S. Patent No. 4,767,628 discloses a composition comprising an active acid-stable polypeptide and polylactide which, when placed in an aqueous physiological environment, releases it substantially in a monophasic manner at an approximately constant rate peptide. US Patent No. 4962091 discloses a microsuspension of water-soluble macromolecular polypeptides in a polylactide matrix. U.S. Patent Nos. 4,849,228 and 4,728,721 disclose a biodegradable high-molecular-weight polymer, which is characterized in that the content of water-soluble low-molecular-weight compounds is less than 0.01mol/100g of high-molecular-weight polymers. The calculation is based on the assumption that this compound is a unitary acid. US Patent Nos. 4,902,515 and 4,719,246 disclose polylactide compositions comprising poly(R-lactide) segments linked to poly(S-lactide) segments. US Patent No 4990336 discloses a multi-stage sustained release system comprising allergen extracts encapsulated in the form of microspheres, which are bioerodible encapsulated polymers that allow the allergen to be released in stages. Sustained release. This system consists of a first part of an allergen extract and a second part, by injection, the first part is released in a manner in which the initial allergenicity is minimized, producing a and Normally similar modest local reactions are observed with low doses of conventional allergens, while the second part provides substantially higher doses of allergen extracts which would produce a severe reaction in patients if not Release the first part of the allergen extract. US Patent No. 4,897,268 discloses microencapsulated delivery systems in which ingredients are encapsulated in biodegradable copolymer excipients formulated in varying molar ratios so that the ingredients are delivered at a constant rate over an extended period of time. Thus, different means of making and using microspheres are known and can readily be used for the purposes of the present invention.

Microspheres of the present invention also include liposomes. Compositions suitable for forming liposomes are well known in the technical literature and compositions are abundant in the art. Preferred lipid compositions are those that become phospholipids, such as phosphatidylcholine (a fatty acid derivative containing 12-20 carbon atoms) (especially 16-20 carbon atoms), phosphatidylserine , phosphatidylinositol, phosphatidylethanolamine, phosphatidylglycerol and phosphatidic acid. These phospholipid compounds may be used alone or in combination. It is especially advantageous to use synthetic or natural distearoylphosphatidylcholine (DSPC) or mixtures of phosphatidylcholines, and mixtures of phosphatidylserine (PS) or phosphatidylglycerol (PG). Advantageously, these liposomes are composed of the above-mentioned phospholipid mixture, in this mixture, generally 7 times the volume of DSPC or phosphatidic acid choline (PC) to 1-10 times the volume, preferably 3 times the volume of PS. The biological activity of the liposomes containing the derivatives of the present invention proved to be equally good when they were presented as unilamellar lipids or as multilamellar lipids. Preferably, the size of the liposome particles is greater than or equal to 0.1 μm, eg, between 1-10 μm.

The compounds of the present invention can be used as modulators of non-specific antimicrobial resistance for systemic enhancement of immune responses and non-specific immunity.

Thus, this suggests, for example, curative treatment or supportive therapy (i.e., together with further specific or supportive forms of treatment) for symptoms of decreased immune response, especially cellular and humoral immune responses and decreased symptoms of delayed-type hypersensitivity reactions. ), and further in the treatment of conditions that often require modulation of the immune response.

It is particularly useful in the curative treatment or supportive care of pathological conditions associated with autoimmune deficiency or with deficiencies encountered in elderly patients or patients with severe burns or systemic infections.

The compounds of the invention are further useful in the curative or supportive treatment of viral infections such as disseminated herpes and disseminated varicella infections, HIV infections and malignancies.

Slow-release hCG can be considered for RNA and DNA viruses. This includes, but is not limited to hepatitis virus, herpes virus, influenza virus and Rift Valley fever virus.

It will be apparent to one of ordinary skill in the art that the exact amount of active ingredient necessary to produce a given result will vary with the particular compound, the size, and the age and condition of the subject to be treated. These quantities can be readily determined using routine methods known to those of ordinary skill in the art.

The adjuvanted compositions and vaccines of the invention are generally administered by injection. However, easier methods of administration, such as oral administration, can also be devised. When the composition of the present invention is directly used for clinical treatment and prevention, it has two forms of oral and parenteral preparations. The term "parenteral" includes subcutaneous, intravenous, epidural, gavage, intramuscular, delivery pump or infusion forms. These compositions may also be administered intraarticularly, intrasynovially, intrathecally, periosteally, intratumorally, peritumorally, intralesionally, perilesionally, sublingually, buccally, transdermally, topically or by inhalation without limitation. apply. It can also be used as a dressing on wounds or lesions. However, a particularly preferred mode of administration of such compositions is oral. When taken orally, the composition of the present invention can be administered alone or combined with pharmaceutically acceptable carriers to make pharmaceutical preparations, such as capsules, pills, gummies, tablets, straw sugar, sachets, tea bags, granules, powders , coated tablets, sugar-coated tablets, dry paste tablets, sugar cubes, gums, hydrogels such as particles of hydrophilic hygroscopic polysaccharides, foams, suppositories, inhalants, juices, shakes, chewing gum, toothpaste, tooth powder, mouthwash Powder, Confectionery and Emulsion.

Suitable pharmaceutical carriers include fillers, binders, lubricants, disintegrants, accelerators and wetting agents. Fillers such as lactose, sucrose, mannitol, glucose, starch, sorbitol, glycine, calcium phosphate and microcrystalline fibers; binders such as starch, casein, gelatin, acacia, glucose, sucrose, sorbitol, mannitol , tragacanth gum, hydroxypropyl cellulose, hydroxypropoxymethyl cellulose, carboxymethyl cellulose, 2-methyl-5-vinylpyridine/methacrylic acid/ethacrylate copolymer, Polyvinylpyrrolidone and sodium alginate, alginate gum; lubricants such as stearic acid, hardened oil, magnesium stearate, calcium stearate, polyoxyethylene monostearate, talc, silicon oxide, and polyethylene glycol ; disintegrants such as potato starch and starch containing surfactants, etc.; accelerators such as magnesium sulfate; wetting agents such as sodium lauryl sulfate.

The compositions of the invention can also be administered in the form of liposomes. Liposomes or artificial lipid vesicles are generally derived from phospholipids or other lipid substances, as is known in the art. They also contain muramyl peptides, metabolizable oils, optionally with added emulsifiers. Monolamellar or multilamellar hydrated liquid crystals dispersed in aqueous media to form liposomes. A typical manufacturing process for a liposomal formulation consisting of liposomes containing the encapsulating composition of the invention involves hydrating the lipid or liposome with a solution of the material to be encapsulated, providing multiple portions of dry lipid or dry liposomal formulations, then hydrate the multiple parts separately with a solution containing the material to be encapsulated, and combine each part together to form a single liposomal formulation, thus forming the A liposome formulation consisting of liposomes of the encapsulating material. Any nontoxic physiologically acceptable metabolic lipid can be used to form liposomes. The present compositions in liposome form include, in addition to the compound of the present invention, stabilizers, preservatives, excipients, and the like. Preferred lipids are phospholipids and phosphatidylcholines (lecithins), either natural or synthetic. Methods of preparing liposomes are well known in the art. For example, cochleate contains biologically relevant molecular components, namely negatively charged lipid components and divalent cationic components. Cochleate has an extended shelf life, even in the dry state. Ingestion of cochleate is beneficial.

For the above meaning, the dosage to be used will depend on the nature and severity of the disease to be treated, the mode of administration and the form of the compound administered. For an average subject, suitable doses are 100 IU to about 20000 IU, administered once or in divided doses. Repeated dosing may conveniently be effected one to three times a day or less frequently, such as once every three days, once a week or once every two weeks, or once a month, or even once every three months. In the case of repeated administration, the specified unit dose of the compound of the present invention is 100 IU to about 10000 IU per injection, preferably about 1000 to 5000 IU. Doses may also be raised to about 20,000 IU for one administration if therapeutically necessary. According to the product instructions provided by hCG commercial preparation manufacturers, those skilled in the art can easily convert the IU unit of hCG into a weight unit, and vice versa.

The compositions of the present invention can also be used in a variety of other methods not related to the therapeutic indication. For example, for the detection of hCG or hCG antibodies, the compositions can be used as labeled or unlabeled reagents in various immunoassays, biological assays, and the like. Suitable labels include radioisotopes, enzymes, fluorescent molecules, chemiluminescent labels, enzyme substrates or cofactors, enzyme inhibitors, particles, dyes, and the like. These labeled reagents can be used in many well-known assays such as radioimmunoassays, enzyme-linked immunoassays such as ELISA, fluorescent immunoassays, etc.

The present invention also includes the concept of using instant compositions and drugs or compounds commonly used in the art for different disease categories. In the aforementioned compounds, the following classes and/or members of these classes are active ingredients, belonging to: adrenocorticosteroids, adrenocorticoinhibitors, aldosterone antagonists, amino acids, anabolics, androgens, anti-AIDS drugs , anthelmintics, anti-acne agents, anti-adrenal agents, anti-allergic agents, anti-amoeba drugs, anti-androgenic drugs, anti-anemia, anti-angina pectoris, anti-arthritic agents, anti-asthma drugs, anti-atherogenic agents , antibacterial, anticholera, anticholelithogenic, anticholinergic, anticoagulant, anticoccidial, antidiabetic, antidiarrheal, antidiuretic, antidote, antiestrogens, antifibrinolytics, Antifungal Agent, Antiglaucoma Agent, Antihemophilic Agent, Antihemorrhagic Agent, Antihistamine Agent, Antihyperlipidemic Agent, Antihyperlipoproteinemic Agent, Antihypertensive Agent, Antihypotensive Agent, Antiinfective Agent , Antitopic Infectious Agents, Antiinflammatory Agents, Antikeratotic Agents, Antimalarial Agents, Antimicrobial, Antimitotic, Antifungal Agents, Antineoplastic Agents, Antineutropenic Agents, Antiparasitic Agents, Antiperistaltic Agents , anti-pneumocystic drugs, anti-proliferative agents, anti-prostatic hypertrophy agents, anti-protozoal drugs, anti-pruritic agents, psoriasis drugs, anti-rheumatic drugs, anti-schistosomiasis drugs, anti-seborrheic agents, anti-secretory agents, sedatives Analgesic, anticoagulant, antitussive, antiulcer, antiurolithiasis, antiviral; appetite suppressant, benign prostatic hyperplasia treatment, bone resorption inhibitor, bronchodilator, carbonic anhydrase inhibitor, cardiac depressant Medicine, cardioprotective agent, cardiotonic agent, cardiovascular agent, choleretic agent, cholinergic drug, cholinergic agonist, cholinesterase inactivator, coccidial agent; auxiliary drug for diagnosis, diuretic, ectocidal Parasitic Drug, Enzyme Inhibitor, Estrogen, Fibrin, Oxygen Radical Scavenger; Glucocorticoid; Gonad Stimulator, Hair Growth Stimulator, Hemostatic Agent, Hormone, Hypocholesterolemic, Hypoglycemic, Hypolipidemic Hypotensive, Immune Agent, Immunomodulator, Immunomodulator, Immunostimulator, Immunosuppressant, Impotence Treatment Adjunct, Inhibitor, Keratolytic, LHRH Agonist, Hepatic Disorder Therapeutic, Luteolysin , mucolytic, mydriatic, nasal decongestant, neuromuscular blocking agent, nonhormonal steroid derivative, oxytocin, plasminogen activator, platelet activating factor antagonist, platelet aggregation inhibitor, potentiator , progesterone, prostaglandin, prostaglandin growth inhibitor, prothyrotropin, lung surface, radioactive substance, modulator, dilator, redistribution agent, scabicide, sclerosing agent, selective adenosine A1 antagonist, steroid Inhibitor, inflammatory multiple sclerosis, potentiator, thyroid hormone, thyroid suppressant, thyromimetic, amyotrophic unilateral sclerosis agent, Paget's disease agent, unstable angina agent, uricosuric agent, vasoconstrictor, vasodilation Agents, trauma medicines, wound healing agents and xanthine oxidase inhibitors, etc.

Those compounds useful in the present invention can be delivered as a drug cocktail. The so-called cocktail is any compound mentioned above mixed with the compound of the present invention. Such mixtures need not be physically mixed, and the drugs may be administered separately, sequentially or simultaneously.

Of particular interest besides AIDS drugs are anticancer drugs which can be administered with the compositions of the invention. Antineoplastic drugs include but are not limited to the following drugs: aschevermectin; aclarmycin; Acodazole Hydrochloride; AcrQnine; ; Aminotropin; Amacridine; Anasulazole; Emmycin; Asparaginase; Asperlin; Azacitidine; Azatepa; Azidomycin; Baimastat; Benzotepa Bisantrene Hydrochloride; Bisnafide Dimesylate; Bisnafide Dimesylate; amine; carbetim; carboplatin; nitrosourea nitrogen mustard; demethyldaunorubicin hydrochloride; kezolexine; Cedefingol; chlorambucil; Cirolemycin; cis-platinum ammonia; claribin; Crisnatol Mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine; Dexomaplatin; Dezaguanine; Dezaguanine Mesylate; Dezaquinone; Taxotere; Adriamycin; Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate; Methylhydrotestosterone Propionate; Azomycin; Edatrexate; Eflomithine Hydrochloride; Elsamitrucin; Enloplatin; Emprubamate; Epiripridine; Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride; Estramustine; Phosphoresstramustine Sodium; ; Etoposide phosphate; Etoprine; Fadrozole hydrochloride; Fazarabine; Fenretinide; Fluorouracil deoxynucleoside; Fludarabine phosphate; ; gemcitabine; gemcitabine hydrochloride; gold Au198; hydroxyurea; idarubicin hydrochloride; ifosfamide; imofosine; alpha-2a interferon; alpha-2b interferon; alpha-n1 interferon; β-Ia interferon; γ-Ib interferon; Isoproplatin; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; Leuprolide acetate; Liarozole Hydrochloride; Stine; loxoanthrone hydrochloride; masoprofen; maytansine; dichloromethyldiethylamine hydrochloride; megestrol acetate; megestrol acetate; phenylalanine mustard; Lier; Mercaptopurine; Methotrexate; Methotrexate Sodium; Metoprine; ; Mitospex; Ortho-Drip; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Nogamycin; Omaplatin; Sulfinyl Pyridine; Paclitaxel; Nemustine; Pelomycin Sulfate; Pifosfamide; Pipolbromide; Piposufan; Piroxantrone Hydrochloride; Miramycin; Plomestane; Porfimer Sodium; Porphyrin Prednimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Triquinone; parfosate Sodium; sparsomycin; germanospiramine hydrochloride; spiromustine; spiroplatinum; streptigrin; streptozocin; strontium chloride Sr 89; Tecogalan Sodium; Tegafur; Tiloxantrone Hydrochloride; Temoporphine; Zamin; topotecan hydrochloride; toremifene citrate; menordone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; trospectrelin; Uramustine; Uretipai; Vapretide; Visodal; Vinblastine Sulfate; Vinbristine Sulfate Sodium; Vindesine; Vindesine Sulfate; Vinbidine Sulfate; Vinblastine Sulfate ; Vinblastine sulfate; Vinorelbine tartrate; Vinblastine sulfate;

Other antineoplastic compounds include: 20-epi-1,25-dihydrovitamin D3; 5-ethynyluracil; abiraterone; Interleukin-2; ALL-TK antagonist; hexamethylmelamine; amustine; amidox; amifostine; aminolevulinic acid; amrubicin; atrsacrine; anagrelide; anasulazole; andrographolide ; angiogenesis inhibitor; antagonist D; antagonist G; antarelix; anti-doralizing morphogenetic protein-1; antiandrogen; prostate cancer; Bacterin; programmed cell death gene modulator; programmed cell death regulator; apurinic nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; 1; axinastatin2; axinastatin 3; azasetron; azatoxin; diazotyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta-lactam derivatives ; β-alethine; subaclacithromycin B; betulinic acid; bFGH inhibitors; ; Budotitanium; Butylthionine Thioxamine; Hercules Ointment; Calphostin C; Camptothecin Derivatives; Canarypox IL-2; Capecitabine; Carbamoyl-Amino-Triazole; Carboxyamino Triazoles; CaRest M3; CARN700; cartilaga-derived inhibitors; kazelexine; casein kinase inhibitor (ICOS); chestospermine; cecropin B; cetrorelix; hydroporphenols; chloroquinoxaline sulfonamides ; cicaprost; cis porphyrin; cladribine; clomid analogs; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogs; conagenin; Derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexifosfamide; Quinone; Escidin B; didox; Diethylnorspermine; Dihydro-5-azacytidine; Dihydropaclitaxel, 9-; Diaminooxalyl; Diphenylspiromustine; Docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocannycin SA; ebselen; ecomustine; edrecolomab; Amino acid; Elemene; Etifluridine; Epirubicin; Apretide; Estramustine analogues; Estrogen agonists; Estrogen antagonists; Etanidazole; Etoposide phosphate; Emansida; Fadrozole; Fazarabine; Fenretinide; Filgrastim; fmasteride; flavopiridol; flezelastine; fluasterone; fludarabine; ; formustine; gadolinium taxaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitor; 21-deoxy-21,21-difluorocytosine; glutathione inhibitor; hepsulfam; Methylenediacetamide; hypericin; ibandronic acid; idarubicin; edoxifene; idramantone; imofosin; ilomastat; imidazoacridones; imiquimod; immunostimulatory peptide ; Insulin-like Growth Hormone-1 Receptor Inhibitor; Interferon Agonist; Interferon; Interleukin; Iodobenzylguanidine; Iododoxorubicin; B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; Lin + estrogen + progesterone; leuprolide; levamisole; liarozole; linear polyamino analogs; lipophilic diglycopeptide; lipophilic platinum compound; lissoclinamide 7; Nidamine; loxoanthrone; lovastatin; loxoribine; letotecan; Texas porphyrin lutetium; lysofylline; cleavage peptide; maytansine; glycomycin A; marimastat; ; maspin; matrix lysin inhibitors; matrix metalloproteinase inhibitors; menoril; Melbaron; meterelin; methioninase; metoclopramide; MIF inhibitors; mifepristone; Miter Fuxin; mirimostin; mismatched double-stranded RNA; Mitoguanidine hydrazone; dibromodulcitol; mitomycin analogs; sargragrastim; monoclonal antibody; human chorionic gonadotropin; monophospholipid A very mycobacterial cell wall sk; mopidamol; multi-drug resistance gene inhibitor; multi-tumor inhibitor 1 basic therapy; mustard anticancer agent; mycaperoxide B; Mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; ; nemorubicin; neridronicacid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulator; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotide ; ondansetron; ondansetron; ondansetron; oracin; oral cytokine inducer; omaplatin; osaterone; oxaliplain; oxaunomycin; paclitaxel analogs; paclitaxel derivatives; Phosphonic acid; Panaxatriol; panomifene; ; phenazinomycin; phenylacetic acid; phosphatase inhibitors; picibanil; ergocarpine hydrochloride; pirarubicin; picrexine; placetin A; placetin B; lysozyme activator inhibitors; Triaminocomplex; Pofemet Sodium; Methylmitomycin; Propylbis-Acridone; Prostaglandin J2; Proteasome Inhibitor; Protein A-Based Immunomodulator; Protein Kinase C Inhibitor; Protein Kinase C inhibitors; smiling algae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purines; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene cross-linked; raf antagonists; Joan; ras farnesyl protein transferase inhibitor; ras inhibitor; ras-GAP inhibitor; retelliptinedemethylated; rhenium Re 186 etidronate; lisoxin; ribozyme; ; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; agent; signal transduction regulator; single-chain antigen-binding protein; sizoran; D; spiromustine; splenopentin; spongin 1; squalene; stem cell inhibitor; stem cell division inhibitor; stipiamide; stromelysin inhibitor; sulfmosine; hyperactive vasoactive intestinal peptide antagonist; suradista; Suramin; swainsonine; synthetic glycosaminoglycans; tamustine; tamoxifen methiodide; tauramustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; Temoporphine; Diamond Donatine; Epipodophyllotoxin Thiophene Glycoside; Tetrachlorodecaoxide; Tetrazomine; Thaliblastine; Thalidomide; Thiocoraline; Thrombopoietin; Thymopoietin receptor agonist; thymotrinan; thyrotropin; tin ethyl etiopurpurin; tirapazamine; titanocene dichloride; topotecan; topsentin; factor; translation inhibitor; tretinoin; triacetyluridine; tricilibine; trimetrexate glucuronide; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitor; tyrosine Acid phosphorylation inhibitor; UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonist; vapreotide; variolin B; vector system; erythrocyte gene therapy; velaresol; veramine; verdins; Viterporphin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone;

It is also an object of the present invention to formulate formulations that do not contain hCG but contain other biologically active water-soluble proteins and peptides. Such an active water-soluble protein is a growth hormone or a somatotropin such as human growth hormone (HGH), bovine growth hormone (BGH or BST), porcine growth hormone (PGH or PST) and their analogs and derivatives substances, as well as epidermal growth factor (FGF) and its analogs. Other proteins that may be considered are interleukins, interleukin receptors, interleukin receptor agonists, chemokines and interferons. For example, interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon alpha-N1, interferon alpha-N3, interferon beta, interferon beta-1 al; interferon beta-1b, gamma-1a Interferon, gamma-1b interferon, omega interferon, tau interferon, interleukin-1, interleukin-1 alpha, interleukin-1 beta, interleukin-10, interleukin-11, interleukin -12, Interleukin-15, Interleukin-2, Interleukin-3, Interleukin-4, Interleukin-5, Interleukin-7, Interleukin-8, MIP-1α and β , RANTES et al. In addition, proteins may also be selected from blood cell growth stimulating factors and their precursors, erythropoietin (EPO) and analogs thereof. Other equally required proteins are parathyroid hormone (PTH), selenoprotein P, cystatin B and its hepatic thiol protease inhibitor analogue, endotoxin neutralizing protein, lymphocyte migration inhibitory factor ( LIF), mast cell growth factor (MGF), megakaryocyte stimulating factor (MGDF), granulocyte macrophage colony stimulating factor (GM-CSF), genofibrate, alpha calcitonin, beta calcitonin, tumor necrosis factor (TNF ), tumor invasion inhibitors, TGF-β-type cytokines, trans-acting regulatory proteins (TAT's) of AIDS and other retroviruses, protease inhibitors and BPC 157, lipid-lowering hormones, and analogs of these proteins and Variants. Also proteins to consider are; Insulin, Glucagon, Gastrin, Angiotensin, Secretin, Prolactin, Thyrotropin, Melanostimulating Hormone, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH) , thyrotropin (TSH), thrombopoietin (TPO), luteinizing hormone, human menopausal gonadotropin, vasopressin, oxytocin, prorelin, corticotropin, SOD, urokinase and Lysozyme. One skilled in the art will recognize that other cytokines are well known and equally suitable for use in the compositions of the invention. Not limited to the biologically active proteins listed above, other polypeptides are also contemplated, such as G-CSF, M-CSF, LIF, inhibin A, inhibin B, activin A, activin B, NAP-1 , MCP-1, MIP-1α, MIP-1β, MIP-2, SISβ, SISδ, SISε, PF4, PBP, γIP-10, MGSA, aFGF, bFGF, KGF, PDGF-A, PDGF-B, PD-ECGF , INS, IGF-I, IGF-II, NGF-β, GRO/MGSA, PF4, PBP/CTAP/β. TG, IP-10, KC, 9E3, MCAF, ACT-2/PAT 744/G26, LD-78/PAT 464, RANTES, G26, I309, JE, TCA3, ICAM-1, ICAM-2, LFA-1, LFA-3, CD72, CTAPIII, ENA-78, GRO, I-309, PF-4 and LD-78.

In addition to the above proteins, other target proteins encoded by the genes listed in Table 1 are also contemplated for use in the composition of the present invention.

Table 1 name The sequence number of the gene fragment in Genebank Length (start-end) bp MmRad51; yeast DNA repair protein, Rad51 and RecA of Escherichia coli are homologous proteins DT3473 855-1199 interleukin-8 receptor D17630 664-1022 α-catenin D25281 1276-1594 BST-1; lymphocyte differentiation antigen CD38 D31788 674-1014 oncoprotein M D31942 1017-1360 CSA receptor L05630 841-1165 Heparin-binding EGF-like growth factor (diphtheria toxin receptor) L07264 258-673 Fms-associated tyrosine kinase 3; Flt3/Flk2 ligand U04807 46-418 CD27; member of the lymphocyte-specific NGF receptor family L24495 596-846 Basic Fibroblast Growth Factor Receptor (bFGF-R) M28998 200-583 granulocyte colony stimulating factor receptor M58288 251-529 Growth/differentiation factor 1 (GDF-1) (TGF-β family) M62301 2267-2566 δ-PKC; δ-protein kinase C M69042 1740-2011 GA-binding protein beta-2 chain M74517 613-931 CD 40L receptor (TNF receptor family) M83312 417-754 Fas1 receptor (Fas antigen, Apo-1 antigen) M83649 416-736 Interleukin-12(p40) beta chain M86671 652-963 Vascular endothelial growth factor (VEGF) M95200 688-955 Interleukin-11 (Adipogenesis Inhibitor) U03421 196-475 interleukin 15 U14332 605-1057 LIMK; LIM serine/threonine kinase U15159 1376-1699 DAP-1; Anti-cell death defense protein 1 U83628 221-509 CD 30L receptor (lymphocyte activating antigen CD30, Ki-1 antigen) U25416 135-435 Mast cytokine U44725 79-417 CC chemokine receptor (monocyte chemoattractant protein 1) (MCP-1RA) U56819 965-1262 Leukemia inhibitory factor (LIF) X06381 63-366 Intercellular adhesion molecule 1 X52264 1053-1385 class II interleukin-1 receptor X59769 882-1134 corticotropin releasing factor receptor X72305 1411-1748 Hepatocyte growth factor (hepapoitein) X72307 641-965 Keratinocyte growth factor FGF-7 Z22703 63-325 activin type I receptor Z31663 847-1130 transcription factor TFIID D01034 291-556 ZO-1; a tight junction protein, a member of the large complex family, is partially homologous to the Drosophila dIg-A tumor suppressor D14340 3714-4001 ERCC5 excision repair protein; XP-G cells complemented by DNA repair protein (XPG) D16306 1336-1639 Bax; Bcl-2 heterodimerization partner and homologous proteins L22472 172-534 B7-2; T lymphocyte activating antigen CD86; CD28 antigen ligand 2; B7-2 antigen; alternative CTLA4 counter-receptor L25606 570-967 NF-2; Merlin (moesin-ezrin-rootin-like protein); shwannomin; neurofibromatosis class II susceptibility protein L27105 2175-2400 Pim-1 proto-oncogene M13945 2713-2930 Egr-1 zinc finger regulatory protein M20157 399-753 PKC-alpha, protein kinase alpha type M25811 1566-1924 CD44 antigen M27129 789-1141 T lymphocyte activating protein M31042 285-606 Neuron-cadherin (N-cadherin) M31131 1212-1409 Subunit of ATP-dependent DNA helicase II 70 kDa; Thyroid Ku (p70/p80) autoantigen p70 subunit (p70Ku) M38700 274-632 G13, G-alpha-13 guanine nucleotide regulatory protein M63660 2057-2377 transcription factor RelB M83380 1456-1728 microtubule cell adhesion protein 1 M84487 984-1304 ERCC3; DNA repair helicase; DNA-repair protein complemented XP-B cells (XPBC) S71186 1147-1444 CRE-BP1; cAMP response element binding protein 1 S76657 412-748 XRCC1, a DNA repair protein, affects the linking nuclear hormone receptor ROR-α-1 U53228 368-675 14-3-3 protein σ U57311 374-640 prothymosin alpha X56135 186-455 PAX-8 (paired box protein PAX8) X57487 680-1011 Camk IV; Ca2/calmodulin-dependent protein kinase IV (catalytic chain) X58995 1269-1608 Subunit of ATP-dependent DNA helicase II 80kDa; thyroid Ku(p70/p80) autoantigen p80 subunit (p80Ku) X66323 565-875 Ret proto-oncogene (protein encoded by papillary thyroid carcinoma) X67812 2359-2680 Nm23-M2; nucleoside diphosphate kinase B; transferrin; C-myc-related transcription factor X68193 80-454 MAPKK6; MAP kinase 6 (bispecific) (MKK6) X97052 375-711 DNA polymerase alpha catalytic subunit (p180) D17384 563-908 Caspase 3; Nedd2 cysteine protease (positive regulator of programmed cell death ICH-1 homolog protein) D28492 398-694 PSD-95/SAP90A D50621 Angiotensin converting enzyme (ACE) (clone ACE.5) L04946 850-1113 Human Clusterin; Inhibitor of Complement Lysis, Testosterone Inhibits Prostate Messenger 2, Apolipoprotein J; Sulfated Glycoprotein-2 L08235 515-744 adipocyte differentiation-associated protein L12721 404-709 Epidermal Growth Factor Receptor Kinase Substrate EPS8 L21671 1562-1873 Jak3 tyrosine protein kinase, Janus kinase 3 L33768 3123-3426 desmoglein 2 L33779 1317-1691 Stat6; Signaling transcript and activator of transcription 6; IL-4stat; STA6 L47650 2057-2411 Lymphocyte-specific protein tyrosine kinase LCK M12056 1205-1488 ERA-1 protein (ERA-1-993) M22115 723-1062 Homeobox protein 2.1 (Hox2.1) M26283 677-884 Zinc finger X-chromosome protein (ZFX). M32309 2153-2554 WT1; Wilms tumor protein inhibitor M55512 1262-1563 Tristetraproline M57422 262- Nucleobindin M96823 80-357 PAX-5 (B cell-specific transcription factor) M97013 286-629 IFNgR2; interferon gamma receptor second (beta) chain, interferon gamma receptor cofactor 1 (AF-1) S69336 832-1089 Transcription Enhancer Factor (TEF-1) S74227 934-1233 Transcription factor NFAT1 isoform, alpha U02079 1601-1910 DNA-binding protein SATB1 U05252 1101-1380 CCHB3; calcium channel (voltage-gated, dihydropyridine-sensitive L-type) (beta-3 subunit) U20372 351-639 P57kip2; cdk inhibitor kip2 (cyclin-dependent kinase inhibitor 1B), member of the p21CIP1 Cdk inhibitor family; candidate tumor suppressor gene. U20553 989-1272 SnoN; ski-related oncogene U36203 671-1006 Homeobox protein 7.1 (Hox7.1) X14759 740-992 neuronal cell surface protein F3 X14943 1033-1311 GATA-3 transcription factor X55123 858-1125 YB1 DNA-binding protein dipeptidyl peptidase IV X58384 61-294 Fli-lets related proto-oncogene X59421 267-623 RXR-beta cis-11-retinoic acid receptor X66224 1225-1477 C3H Cytochrome p450; Cyp1b1 X78445 295-593 Ubiquitin conjugating enzyme, yeast Rad6 homologue, murine HR6B X96859 51-392 relaxin Z27088 51-365 transcription factor LIM-1 Z27410 1673-1934 DNA topoisomerase I (Top I) D10061 1051-1357 DNA topoisomerase II (TopII) D12513 520-870 GSTPi1; glutathione S-transferase, Pi1; preadipocyte growth factor D30687 62-369 glutathione S-transferase A J03958 54-311 Glutathione S-transferase Mul J04696 13-263 c-Ab1 proto-oncogene L10656 878-1145 A-Raf proto-oncogene M13071 1042-1320 c-Src proto-oncogene M17031 452-758 Cellular retinoic acid binding protein II (CRAB-II) M35523 276-571 Cyclin D2 (G1/S-specific) M83749 781-1074 Cyclin D3 (G1/S-specific) U43844 484-790 Serotonin receptor (Serotonin receptor type 2 (SHT2)) Cyclin D1 (G1/S-specific) S78355 1858-2205 Pur-α transcriptional activator, a sequence-specific ssDNA-binding protein U02098 1082-1309 Cdc2Sa; cdc2SM1; MPI1 (M phase-induced phosphatase 1) U27323 606-986 ERCC-1; DNA excision repair protein X07414 189-484 c-rel proto-oncogene X15842 1729-2064 inhibin alpha subunit X69618 810-1117 glutathione reductase X76341 115-377 Insulin-like growth factor binding protein-3 (IGFBP-3) X81581 474-719 Cyclin A (G2/M-specific) Z26580 701-1009 preproglucagon Z46845 172-531 NF-κB p65, NF-κ-B transcription factor p65 subunit, rel-related polypeptide M61909 101-363 PKC-theta; protein kinase C theta type D11091 658-957 VLA-3α subunit D13867 288-589 NADPH cytochrome p450 reductase D17571 326-605 beta tachykinin D17584 273-523 Kinase D30743 1816-2159 protein tyrosine phosphatase D83966 1060-1426 Jun-D; c-jun-associated transcription factor J05205 737-964 Integrin α7 L23423 2399-2713 Gadd45; growth arrest and DNA damage-inducible protein L28177 144-434 Bcl-xL apoptosis regulator protein (bcl-xLong); Bcl-2 family member L35049 641-906 N-myc proto-oncogene protein X03919 3262-3450 cAMP-dependent protein kinase type I-β regulatory chain M20473 538-750 IRF1, interferon regulatory factor 1 M21065 1-233 HSP86, heat shock 86kDa protein M36830 255-551 LFA-1α; Integrin αL; Leukocyte adhesion glycoprotein LFA-1α chain, antigen CD11A (P180) M60778 1838-2050 APC; Adenomatous polyposis coli protein M88127 4127-4476 Cdc2Sb; cdc2SM2, MPI2 (M-phase-induced phosphatase 2) S93521 1893-2200 Phosphatidylinositol 3-kinase catalytic subunit Rsp27, heat shock 27kDa protein 1 U03560 245-550 Csk; c-Src-1 kinase and negative regulator U05247 645-984 Fas1; Fas antigen ligand, mouse generalized lymphoproliferative disease gene (gld) U06948 168-488 MAPK; MAP kinase; p38 U10871 465-780 P19ink4; cdk4 and cdk6 inhibitor U19597 228-516 Elf1 Ets Family Transcription Factors U19617 1585-1902 CRAF1; TNF receptor (CD40 receptor) related factor; TRAF related U21050 1225-1466 SPI3, serine protease inhibitor (serpin); similar to human protease inhibitor 6 (placental thrombin inhibitor) serine protease inhibitor U25844 915-1230 RIP cell death protein, Fas/Apo-1(CD95) interactor, including death domain U25995 1945-2223 SLAP; src-like adapter protein, Eck receptor tyrosine kinase-associated protein U29056 109-427 Atm; mouse ataxia telangiectasia U43678 8989-9170 EB1 APC-binding protein U51196 607-834 TANK; I-TRAF; TRAF family member-related NF-κB activator U51907 135-437 Caspase-11, ICH-3 cysteine protease, upstream regulatory element of ICE U59463 352-686 MIHI DNA mismatch repair protein, MutL homolog U59883 1037-1278 Insulin-like growth factor-IA X04480 183-406 Cell surface glycoprotein MAC-1α subunit X07640 1892-2179 N-ras proto-oncogene; transforming G protein X13664 548-857 L-myc proto-oncogene protein X13945 5287-5590 CD18 antigen beta subunit (leukocyte adhesion LFA-1) (CD3, p150, 95) X14951 1366-1706 C-Fgr proto-oncogene X52191 1305-1538 Integrin α4 X53176 2176-2449 PKC-β; protein kinase Cβ type II X53532 1712-2089 HSP60, heat shock 60kD protein I X53584 1432-1691 mitochondrial matrix protein c-CbI proto-oncogene (adapter protein) X57111 858- Cdc25 phosphatase; guanine nucleotide releasing protein X59868 942- Ezrin; villin 2; NF-2 (merlin)-associated filamentous/plasma membrane-associated protein X60671 1571-1812 Cyclin B1 (G2/M specific) X64713 1184-1447 Integrin α6 X69902 -611 Serotonin receptor 3 (serotoni) X72395 1422-1711 Homeobox protein HOXD-3 X73573 141-362 Cyclin E (G1/S specific) X75888 799- MAPKAPK-2; MAP Kinase-2 Activating Protein Kinase; MAPKAP Kinase 2 X76850 719-987 Fra-2 (fos-related antigen 2) X83971 617-844 Cyclin A1 (G2/M specific) X84311 656-916 DCC; axon growth-inducing factor (netrin) receptor; member of the immunoglobulin gene superfamily, protumor candidate suppressor protein X85788 4193-4508 MHR23A; Rad23 UV excision repair protein homologue, a xerodemia repair complement protein X92410 613-955 MHR23B, Rad23 ultraviolet excision repair protein homologue, xeroderma C pigment group (XPC) repair complement protein X92411 542-807 Integrin beta Y00769 1990-2320 MmRad52; Homolog of the yeast DNA repair protein Rad52 Z32767 159-417 Cyclin G (G2/M specific) Z37110 300-619 Prostaglandin E2 receptor EP4 subtype D13458 1146-1442 interleukin 5 receptor D90205 1389-1739 Epidermal Growth Factor (EGF) J00380 180-505 erythropoietin receptor J04843 1193-1377 insulin receptor J05149 653-1011 P53; tumor suppressor protein, DNA-binding protein K01700 1125-1517 Cf2r, coagulation factor II (thrombin) receptor L03529 762-1154 PTPRG; protein tyrosine phosphatase gamma L09562 1248-1504 DNA-binding protein SMBP2 L10075 4790-5088 interleukin 10 receptor L12120 1762-2110 interleukin 2 receptor gamma chain L20048 1073-1313 L24755 2402-2676 Urine opsonin L33406 1809-2136 Thrombopoietin L34169 652-954 beta-transforming growth factor M13177 772-1075 Granulocyte colony stimulating factor (G-CSF) M13926 86-377 Neuroleukin M14220 1110-1490 Insulin-like growth factor-2 (somatomodulin A) M14951 46-328 beta interleukin 1 M15131 827-1225 c-myb proto-oncogene protein M16449 1212-1513 Tumor necrosis factor beta TNF-beta (lymphotoxin alpha) M16819 461-805 interleukin-1 receptor M20658 2050-2410 CSF-1, M-CSF, colony-stimulating factor-1 X05010 1268-1657 Interleukin-4 receptor (membrane-bound form) M27959 2469-2705 interferon-gamma receptor M28233 1262-1550 interleukin-7 receptor M29697 701-1104 interferon gamma inducible monokine M34815 42-323 interleukin 10 M37897 175-456 NF-κB binding subunit (nuclear factor) (TFDB5) M57999 3122-3417 Tumor necrosis factor receptor 1; TNFR-1 M59378 1961-2376 PDGFRa; Platelet-derived growth factor alpha receptor M84607 474-803 interleukin 9 receptor M84746 795-1086 INOS1; nitric oxide synthase (induced) M87039 3178-3455 interferon alpha-beta receptor M89641 808-1120 Activating transcription factor 4 (mATF4) M94087 416-769 β2-RAR; retinoic acid receptor β2 S56660 589-896 Tie-2 proto-oncogene S67051 1834-2179 IGF-I-Rα; insulin-like growth factor I receptor alpha subunit U00182 489-885 IGFR II; insulin-like growth factor receptor II, cation-dependent mannose-6-phosphate-receptor, elevated in Wilms tumor cells U04710 707-1060 Stat3; APRF; acute phase response factor U06922 1575-1910 U18542 1375-1630 Endothelin b receptor (Ednrb) U32329 379-695 pro-endothelin-3 U32330 703-1008 proplatelet-derived growth factor receptor X04367 2336-2677 CD4 receptor (T cell activating antigen) X04836 1652-1877 interleukin 7 X07962 241-496 macrophage inflammatory protein X12531 25-359 Thrombomodulin X14432 1082-1365 Interleukin 6 (B cell differentiation factor) X51975 1638-1898 androgen receptor X53779 2189-2491 Bone Morphogenetic Protein 4 (BMP-4) (TGFβ Family) X56848 1275-1513 Transferrin receptor protein (p90, CD71) X57349 654-1023 transforming growth factor beta 2 X57413 2227-2541 Glutamate receptors, ionizing AMPAI X57497 1290-1657 TNF55; tumor necrosis factor 1 (55kd) X57796 656-1022 Mdm2; pS3 regulatory protein X58876 1364- Transcription factor I for heat shock genes X61753 203-570 CD40L; CD ligand X65453 545-809 c-Fms proto-oncogene (macrophage colony-stimulating factor 1 (CSF-1) receptor) X68932 2399-2686 B-myb proto-oncogene; myb-associated protein B X70472 2109-2456 Ear-2; v-erbA-related proto-oncogene X76654 1065-1376 Tie-1 tyrosine protein kinase receptor X80764 1425-1844 Glutamate receptor, ionizing NMDA2B (ε2) D10651 506-786 Glutamate receptor, ionizing NMDA2A (ε1) D10217 3966-4209 CD7 antigen D10329 28-421 Transcription factor S-II (transcription elongation factor) D00926 518-767 Basic Fibroblast Growth Factor (b-FGF) D12482 290-620 bone morphogenetic protein receptor D16250 1454-1837 G-protein coupled receptor D17292 833-1115 D17407 734-1079 Cdks; cyclin-dependent kinase 5 D29678 552-882 type I TGT-β receptor D25540 1407-1629 kinetin-like protein KIF3B D26077 3519-3722 Kinetin family protein KIF1A D29951 2553-2830 fibroblast growth factor 9 D38258 91-379 neuronal death protein D83698 627-805 Syp; SR-PTP2; Adapter protein tyrosine phosphatase D84372 1229-1543 Interferon regulatory factor 2 (IRF2) J03168 718-976 laminin receptor 1 J02870 368-675 NF-IB protein (transcription factor) D90176 452-791 Jun-B, c-jun-associated transcription factor J03236 514-740 tissue plasminogen activator protein J03520 622-1020 Homeobox protein 4.2 (Rox4.2) J03770 565-945 Nur77 early response protein; Thyroid hormone (TR3) receptor J04113 825-1059 Ets-2 transcription factor J04103 917-1281 c-Jun proto-oncogene (component of transcription factor AP-1) J04115 951-1238 serine protease inhibitor homologous protein J6 J05609 581-855 NGF) K01759 642-901 Cdk4; cyclin-dependent kinase 4 L01640 230-616 Acetylcholine receptor delta subunit K02582 1400-1655 MAPKK1; MAP kinase kinase 3 (bispecific) (MKK1) L02526 1284-1583 GABA-A transporter 4 L04662 960-1341 GABA-A transporter 3 L04663 1010-1320 Vegfr1; Vascular endothelial growth factor receptor 1/Fms-associated tyrosine kinase (Flt1) L07297 1144-1541 adrenergic receptor beta 1 L10084 404-772 Eph3(Nuk) tyrosine protein kinase receptor L25890 2255-2491 MTJ1; a DnaJ-like heat shock protein in mouse tumors L16953 1059-1384 TIMP-3 Tissue Inhibitor of Metalloproteinase-3 L19622 274-592 Insulin receptor substrate-1 (IRS-1) L24563 1027-1304 YY1(UCRBP) transcription factor L13968 1052-1292 Interleukin Converting Enzyme (TCE) L28095 30-269 hepatoma transmembrane kinase ligand L38847 927-1219 voltage-gated Na channel L36179 4179-4505 Bcl-XL and Bcl-2, promote cell death L37296 1079-1375 Jnk stress-activated protein kinase (SAPK) L35236 795-1032 Cytoskeleton epidermal keratin (18 persons) M11686 473-773 Alpha Nerve Growth Factor (α-NGF) M11434 294-494 Epidermal keratin (1 person) M10937 326-683 nicotinic acetylcholine receptors M14537 1226-1568 MDR1; P-glycoprotein multidrug resistance protein, efflux pump M14757 1500-1886 CD2 antigen M18934 354-602 Homeobox protein 1.1 (Hox-1.1) M17192 466-723 fetal myosin basic light chain M19436 205-504 IL-4 M25892 77-310 Rb; pp105; retinoblastoma sensitivity-associated protein (tumor suppressor gene, cell cycle regulatory protein) M26391 2036-2296 Rsk; ribosomal protein S6 kinase M28489 1191-1436 Platelet-derived growth factor (A chain) (PDGF-A) M29464 152-425 (19 people) M28698 194-500 RAG-1; V(D)J recombination activator protein M29475 2155-2404 interleukin-3 receptor M29855 1975-2254 k-fibroblast growth factor M30642 309-577 8-mer binding transcription factor (Oct3) M34381 774-999 Plasminogen Activator Inhibitor M33960 1096-1344 CD3 antigen, delta-polypeptide M33158 73-361 Homeobox protein 2.5 (Hox2.5) M34857 11-277 HSP84, heat shock 84kDa protein M36829 342-736 Mast cell protease (MMCP)-4 M55617 634-992 Erk1, extracellular signal-regulated kinase 1; p44; Ert2 M61177 115-373 P13-Kp85; Regulatory subunit of phosphatidylinositol 3-kinase; Phosphoprotein p85; PDGF signaling pathway member M60651 981-1260 P58/GTA; galactosyltransferase-binding protein kinase (cdc2-associated protein kinase) M58633 1022-1284 Serine protease inhibitor 2 (spi-2) M64086 1499-1754 M64429 1651-2036 Etk1 (Mek4; HEK), tyrosine protein kinase receptor HEK M68513 2681-2915 RAG-2; V(D)J recombination activator protein M64796 671-944 type IV collagenase M84324 696-1040 Interleukin-6 receptor beta chain, membrane glycoprotein gp130 M83336 1423-1741 α-cardioglobin heavy chain M76601 2094-2391 retinoic acid receptor RXR-γ M84819 701-1082 granulocyte macrophage colony stimulating factor receptor M85078 904-1289 GABA-A receptor alpha-1 subunit M86566 1251-1606 Endothelial ligand of L-selectin (GLYCAM1) M93428 182-541 Integrin β7 subunit M95633 2142-2423 DNase I U00478 665-871 Cortacin, protein tyrosine kinase substrate U01384 426-653 adenosine A2M2 receptor U05672 491-735 DNA ligase 1 U04674 1678-2054 adenosine AIM receptor U05671 302-673 non-muscle myosin light chain 3 Cathepsin H U06119 325-694 Stat1; signal transducer and activator of transcription U06924 1749-2104 P21/cip1/Waf1; cdk inhibitor protein U09507 9-403 Cdk7; M015; Cyclin-dependent kinase 7 (homolog of xenopus M015 cdk-activating kinase) U11822 454-824 P27kip1; G1 cyclin-Cdk protein U10440 270-454 Kinase Inhibitor, p21-Related Gem; Induced immediate early protein; Ras family member U10551 220-471 VRL; Von Hippel-Lindau tumor suppressor protein U12570 885-1111 Cek5 receptor protein tyrosine kinase ligand U12983 1037-1287 Glutathione peroxidase (plasma membrane protein); selenoprotein U13705 766-1046 Integrin alpha 5 (CD51) U14135 2170-2516 Ski proto-oncogene U14173 707-1037 Ablphilin I (abi-1) similar to HOXD3 U17698 351-585 BAG-1, a bcl-2-binding protein with anti-cell death activity U17162 17-334 Shc transforming adapter protein U15784 1220-1451 Src homolog 2 (SR2) protein, SRB- MAPKK4; MAP kinase kinase 4, Jnk-activating kinase 1, (JNKK1, SEK1, MKK4) U18310 1380-1749 transcription factor LRG-21 U19118 618-966 interferon-inducible protein 1 U19119 1342-1636 A20 zinc finger protein, apoptosis inhibitor U19463 1952-2293 P18ink4; cdk4 and cdk6 inhibitor U19596 16-284 I-κB (I-κB)βDv12; disheveled-2 tissue U19799 419-778 polar protein U24160 1205-1578 Nuclear factor associated with P45 NF-E2 U20532 1429-1759 MSH2 DNA mismatch repair protein, Muts homolog 2 U21011 2150-2490 GapIII, GTPase-activating protein U20238 328-644 Syk tyrosine protein kinase (activated p21cdc42Rs kinase (ack)) U25685 1235-1524 P107; RBL1; Retinoblastoma gene product-associated protein p107 (cell cycle regulator) U27177 1973-2365 PMS2 DNA mismatch repair protein, yeast PMS1 homolog 2 U28724 749-1013 Limphotoxin receptors (TNFR family) U29173 1415-1668 BRCA1; breast/ovarian cancer susceptibility locus 1 product U31625 5126-5430 Pml; murine homolog of the leukemia-associated PML gene U33626 1667-2064 transducin beta-2 subunit U34960 515-834 I-κB (I-κB) βα chain U36277 541-823 TRAIL, TNF-related apoptosis-inducing ligand; U37522 981-1288 Apo-2 ligand P130; Retinoblastoma gene product-associated protein Rb2/p130 (cell cycle regulator) U36799 970-1321 CACCC box binding protein BKLF U36340 826-1065 FAF1; Fas-binding protein factor, activator of apoptosis U39643 423-681 zinc finger transcription factor RU49 U41671 1229-1591 GTBP; G/T mismatch binding protein; MSH6 U42190 1477-1769 βPLC, phospholipase Cβ3 U43144 1933-2271 Frizzled-3; Drosophila tissue gene Frizzled homolog 3; dishevelled receptor U43205 2037-2285 MAPKK3; MAP kinase kinase 3 (dual specificity) (MKK3, MEK3) U43187 1436-1742 Myeloblastin, trypsin-chymotrypsin-related serine protease U43525 503-807 Zinc finger Kruppel-type Zfp92 U47104 578-896 TDAG51; and Fas(CD95) expression coupled TCR signaling U44088 729-1042 Class II POU domain-binding factor I U43788 610-884 ALG-2; calcium-binding protein required for programmed cell death U49112 527-861 unconventional myosin VI U49739 3784-4021 Transcription factor CTCF (11 zinc fingers) U51037 1625-1911 transcription factor C1 U53925 3895-4227 Madr1; mSmad1; anti-dpp protein maternal (Mad) murine homolog; TGF-β signaling protein-1 (bsp-1); candidate tumor suppressor gene U58992 238-476 Bcl-W regulator of apoptosis; Bcl-2 family member U59746 153-368 U60530 584-820 Cyclin C (G1 specific) U62638 714-986 Mph-1 repressor of nuclear transcription of Hox genes U63386 1621-1884 Rad50; DNA repair protein U66887 1383-1707 Fyn proto-oncogene; Src family member U70324 584-882 c-myc proto-oncogene protein X01023 379-667 c-Fos proto-oncogene; transcription factor AP-1 component fos cell oncogene V00727 482-734 Cathepsin L X06086 267-588 Glutamate receptor channel subunit gamma X04648 41-408 c-Fes proto-oncogene X12616 2342-2598 Cytotoxic protease 2 (B10) X12822 439-686 Homeobox protein 3.1 (Hox3.1) X07439 449-722 Homeobox protein 2.4 (Hox2.4) X13721 1949-2284 Fos-B; c-fos-related protein fosB X14897 920-1278 Plasminogen Activator Inhibitor 2 X16490 674-978 c-ErbA oncogene; thyroid hormone receptor X51983 400-675 vimentin X51438 868-1096 HMG-14 non-histone chromosomal protein X53476 643-1017 Macrophage inflammatory protein 2α (MIP2α) X53798 14-352 Bone Morphogenetic Protein 7 (BMP-7) (Osteogenic Protein 1) X56906 670-971 Transcription factor SPIP (POU region transcription factor) X56959 866-1128 Homeobox protein 8 (Hox8) X59252 826-1132 fibroblast growth factor receptor 4 X59927 2446-2820 Rac1 mouse homolog X57277 425-651 transcription factor UBF X60831 689-993 kinesin heavy chain X61435 1898-2182 CCAAT-binding transcription factor (C/EBP) X61800 904-1150 TIMP-2; Tissue Inhibitor of Metalloproteinase-2 X62622 1236-1468 Ets-associated protein PEA3 X63190 1702-2040 Vav; GDP-GTP exchange factor; proto-oncogene X64361 1083-1351 PAX-6 (paired box protein) X63963 1081-1325 X66032 874-1236 Chop10; murine homolog of Gadd153 (growth arrest and DNA damage-inducible protein) X67083 17-332 PD-1; possible inducer of cell death; member of the Ig gene superfamily X67914 1481-1734 Inhibin βA subunit (TGFβ family) X69619 1064-1304 Vegfr2; KDR/FLK1 vascular endothelial growth factor tyrosine kinase receptor X70842 1394-1721 Protease nexin 1 (PN-1) X70296 746-985 MRE-binding transcription factor X71327 552-916 Activin-1 140kDa subunit (replication factor C140kDa) X72711 4137-4375 DP-1 (DRTF-polipeptidel) cell cycle regulatory transcription factor X72310 925-1305 serotonin (serotonin) receptor 1c X72230 982-1314 Gelatinase B X72795 599-954 XPAC; Xeroderma pigmentosa group A error-correcting protein X74351 447-669 Integrin alpha (CD49b) X75427 1595-1976 Growth/differentiation factor 2 (GDF-2) X77113 939-1329 Insulin-like growth factor binding protein 4 (IGFBP-4) Insulin-like growth factor binding protein 1 (IGFBP-1) X81579 27-256 IGFBP-2; insulin-like growth factor binding protein 2, autocrine and/or paracrine growth promoter X81580 449-817 Insulin-like growth factor binding protein 5 (IGFBP-5) X81583 461-824 Insulin-like growth factor binding protein 6 (IGFBP-6) X81584 701-1039 A-myb proto-oncogene; myb-associated protein A X82327 1017-1334 membrane-type matrix metalloproteinase X83536 877-1101 Elk-1 ets related proto-oncogene X87257 1498-1680 E2F5 transcription factor X86925 426-728 Lbx-1 transcription factor X90829 1000-1306 P-selectin (glycoprotein-1) X91144 1095-1323 transcription factor SEF2 X91753 755-1054 macrophage C-mannose receptor Z11974 807-1197 Rab-2 ras-related protein X95403 232-505 Glutathione S-transferase (theta type 1), phase II crosslinking enzyme X98055 14-298 Zexin; LIM domain protein; α-actin-binding protein -1812 Met proto-oncogene Y00671 3646-3933 c-Kit proto-oncogene (mast cell/stem cell growth factor receptor tyrosine kinase) Y00864 2867-3181 Transcription factor BARX1 (homeodian transcription factor) Y07960 723-973 PLCγ; Phospholipase Cγ X95346 180-516 Stromelysin-3; Matrix metalloproteinase-11 (MMP-11) Z12604 1463-1806 Serotonin (serotonin) receptor 1eβ Z14224 530-774 Serotonin (serotonin) receptor 2c Z15119 588-940 LDL receptor Z19521 1047-1324 Serotonin (serotonin) receptor 7 Z23107 460-817 c-Mp1; Thrombopoietin receptor; Member of the mematopoietic growth factor receptor superfamily Z22649 1561-1772 DNA polymerase 6 catalytic subunit Z21848 1256-1600 follistatin Z29532 764-1053 Cyclin F (S/G2/M specific) Z47766 2431-2708 Ets-associated protein Sap1A Z26885 1267-1521 Net;ets-associated transcription factor Z32815 1211-1595 Stat5a; mammary factor Z48538 2269-2628 Hck2 murine homolog; Mdk5 murine developmental kinase; Eph-associated tyrosine kinase receptor Z49086 1702-1930 D-factor/LIF receptor D26177 2376-2775 Cytoskeleton epidermal keratin (14 persons) M13806 108-469 R-ras protein, closely related to ras proto-oncogene M21019 215-555 Prolactin receptor PRLR2 M22959 1-328 Blk; B lymphocyte kinase; Src family member M30903 1307-1672 Macrophage inflammatory protein 1β (Act2) M35590 119-445 Alpha-1 protease inhibitor 2, GABA-A transporter 1 M75716 625-969 Bone Morphogenetic Protein 8a (BMP-8a) (TGF-β Family) M97017 788-1139 Krupple-like transcription factor for erythrocytes M97200 783-1171 GATA-binding transcription factor (GATA-4) M98339 81-379 growth factor receptor M98547 1701-2014 Crk Adapter Protein; Retinoid X Receptor Interacting Protein (RIP15) U09419 1388-1682 Cek7 receptor protein tyrosine kinase ligand U14752 504-837 CC CKR-1; CCR-1; CC chemokine receptor type I; macrophage inflammatory protein-1α receptor; MIP-α-R; RANTES-R U29678 168-495 glucocorticoid receptor form A X13358 1527-1816 Anti-DPP protein parent protein (mad homologue Smad1, transforming growth factor beta signaling protein) X83106 464-728 Hck tyrosine protein kinase Y00487 1308-1563 photolyase/blue photoreceptor homolog AB00077 1418-1737 Osp94 osmotic stress protein; APG-1; Hsp70-related D49482 1026-1266 Glucose-regulated protein; 78kDa; Grp78 D78645 167-411 LCR-1; CXCR-4; CXC (SDF-1); Chemokine 4; HIV co-receptor (fusin); G protein-coupled receptor LCR1 homolog; D87747 584-867 Glucose transporter-1, red blood cells M23384 325-653 Iht-3 proto-oncogene; NOTCH family member; NOTCH4 M80456 1846-2145 c-Akt proto-oncogene; Rac-α; protein kinase B (PKB) M94335 604-899 Bak apoptosis regulator protein; Bcl-2 family member Y13231 1509-1786 PS-2; a homolog of the Alzheimer's disease gene U57324 437-783 BRCA-2; Breast cancer susceptibility locus 2 product U65594 649-922 DNA ligase III U66058 2980-3205 Caspase-7; Lice2; LCE-LAP3 cysteine protease U67321 1040-1280 BID; Apoptotic death agonist U75506 452-777 WBP6; pSK-SRPK1; WW domain binding protein 6; SP splicing factor serine kinase U92456 482-774 Cyclin G2 (G2/M specific) U95826 408-688 Ung1; Uracil-DNA glycosylase X99018 444-729 Rab-3b Ras-related protein Y14019 232-562 RNA-activated protein kinase inhibitor, 58kDa U28423 180-487 Golgi 4 transmembrane U34259 742-1060 ATP-binding cassette 8; ABC8; Drosophila CDC42 GTP-binding protein homolog U34920 1011-1319 G25k U37720 1675-1982 Epipodophyllotoxin induces p53 response (Et24) mRNA U41751 1041-1296 Casein kinase II (alpha subunit) U51866 1237-1517 TSG101 tumor susceptibility protein U52945 446-713 Tumor suppressor protein Maspin U54705 251-507 FLIP-1, apoptosis inhibitory protein; FLICE-like inhibitory protein U97076 1476-1811 CamKII; Ca2+/calmodulin-dependent protein kinase II (beta subunit) X63615 1951-2219 Htk; Mdk2 mouse developmental kinase; Eph-associated tyrosine kinase receptor Z49085 2032-2365 glial cell line-derived neurotrophic factor D49921 236-539 CD31 (platelet endothelial cell adhesion molecule 1) L06039 1172-1494 CD22 antigen L16928 2314-2645 Gbx2 L39970 1122-1395 Serine protease CCPI gene (CTLA-1) M12302 585-830 Cathepsin B M14222 384-729 growth hormone receptor M33324 1924-2240 CD28 (B71 receptor) M34563 544-774 estrogen receptor M38651 742-1013 monotypic chemoattractant protein 3 S71251 201-491 CD45-associated protein (CD45-ap, LSM-1) U03856 620-898 orphan receptor U11688 1686-1943 Cannabis receptor 1 (brain) U17985 1091-1437 dystrophic glycan 1 U43512 2267-2505 G protein-coupled receptor U46923 350-671 urokinase-type plasminogen activator X02389 1301-1538 CTLA-4 (Immunoglobulin Superfamily Constituent) X05719 246-519 myogenic factor 5 X56182 232-528 UPAR1; surface receptor for urokinase-type plasmin activator (CD87) X62700 482-756 Serine protease inhibitors 2.4 X69832 621-927 SRY-cassette containing gene 4 X70298 34-311 Bone Morphogenetic Protein 2 (BMP-2) (TGF-β Family) [K02588]P-1-450; dioxin-inducible cytochrome P450[K02588] M10021 3729-4014 Bcl-2; B-cell lymphoma protein 2, inhibitor of apoptosis protein M16506 2125-2367 CD14 antigen M34510 667-931 somatostatin receptor 2 M81832 47-310 dopamine receptor 4 U19880 907-1191 Cannabis receptor 2 (macrophage, CB2) U21681 910-1262 Erf (Ets-related transcription factor) U58533 1286-1613 5-hydroxytryptamine (serotonin) receptor 1b Z11597 1043-1355 Tob antoproliferative factor, interacts with p185erbB2 D78382 540-876 Glutathione S-transferase (microsomal) J03752 185-428 Adenosine A3 receptor L20331 182-382 P55cdc; cell division control protein 20 U05341 1061-1348 AP endonuclease; apurinic/apyrimidinic endonuclease (Apex); Mas proto-oncogene (G-protein coupled receptor) U12273 1894-2150 AT motif binding factor ATBF1 D26046 9807-10112 HMG box transcription factor from testis (MusSox17) D49474 427-662 Ikaros DNA binding protein L03547 627-890 Early B cell factor (EBF) L12147 750-1026 Engrailed protein (En-1) homologue L12703 1323-1554 Engrailed protein (En-2) homologue L12705 1626-1895 transcription factor A10 L21027 499-806 Myocyte nuclear factor (MNF) L26507 1203-1456 Basic domain/leucine zipper transcription factor L36435 872-1073 Tail-type homeobox 1 (Cdx1) M37163 1040-1301 butyrate response factor 1 M58566 768-22 Brain-specific transcription factor NURR-1 S53744 1548-1754 Bm-3.2 POU transcription factor S68377 877-1237 Tail-type homeobox 2 (Cdx2) S74520 1085-1367 cytoplasmic transcription factor NF-E2 U01036 1-241 Gut-specific Kruppel-like factor (GKLF) U20344 1558-1789 Kruppel-like factor LKLF U25096 898-1193 Neuronal helix-loop-helix protein (NEX-1), brain factor 1 (Hfhbf1) U36760 1080-1318 cleft hand/foot gene U41626 92-303 Sim transcription factor U42554 2828-3066 Lost glial cell gene homolog (mGCM1) U59876 727-1080 Sp4 zinc finger transcription factor U62522 1704-1929 heat shock transcription factor 2 (HSF2) X61754 1445-1640 RNA polymerase I termination factor, TTF-1 X83974 3222-3433 Hepatocyte nuclear factor 3/forkhead homolog 8 (HFH-8) L35949 913-1232 SRX box containing gene 3 (Sox3) X94125 212-443 Cot proto-oncogene D13759 696-956 HR21spA; protein involved in DNA double-strand break repair; PW29; calcium-binding protein D49429 103-434 MmLim15; RecA-like gene; DMC1 homolog; meiosis-specific homologous recombination protein D64107 581-781 Erp72 endoplasmic reticulum protein; protein disulfide isomerase-associated protein J05186 1160-1470 HMG1-associated VDJ recombinant signaling binding protein S50213 2263-2531 Gli oncogene, zinc finger transcription factor S65038 104-505 Tiam-1 invasion-inducible protein; GDP-GTP switcher-associated U05245 4329-4628 Sik; Src-related enterokinase U16805 1246-1623 Lfc proto-oncogene U28495 853-1150 oxidative stress inducible protein mRNA U40930 1248-1561 STAM; signal transduction adapter molecule U43900 576-811 ShcC linker; Shc-related; brain-specific U46854 246-601 MmMrella-derived endo/exonuclease U58987 866-1204 PCNA; proliferating cell nuclear antigen; processivity factor X53068 53-320 translin; recombinant hotspot-binding protein X81464 205-431 PA6 matrix protein; RAG1 gene activator X96618 442-749 Sky proto-oncogene (Tyro3; Rse; Dtk) U18342 1927-2286 H-ras proto-oncogene; transport G protein Z50013 1307-1544 ERBB-2 receptor (c-neu; HER2 protein tyrosine kinase) L47239 16-266 ERBB-3 receptor L47240 4-243 Placental ribonuclease inhibitor (angiopoietin) U22516 512-766 Myosin I L00923 2578-2921 Ca2+ binding protein: Cab45 U45977 597-1082 murine bird amino acid decarboxylase M10624 865-1252

Example 1

The compositions of the present invention can be prepared by a number of methods well known to those skilled in the art. In summary, the lipophilic and hydrophilic values required for different applications are as follows: 3-6 water-in-oil emulsifier (such as sorbitan ester + squalene), 7-9 wetting agent; 8-13 water Oil-in-oil emulsifier; 13-15 detergent; 15-18 solubilizer (such as aluminum stearate and magnesium stearate). These values are widely cited in the literature as guidelines for the selection of special purpose emulsifiers. They are designed for use in nonionic emulsifiers. Similar systems were developed for anionic or cationic emulsifiers, but they are less useful than nonionic emulsifiers. The hydrophilic-lipophilic equilibrium numbers for many nonionic emulsifiers have been published. An oil-in-water emulsion containing about 0.5-55% oil, about 0.1-15% emulsifier, about 0.05-5% nonionic surfactant, about 0.00001-10% therapeutic agent and a continuous aqueous phase suitable for this particular usage. The emulsifier in the composition is a phospholipid compound or a mixture of phospholipids selected from phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, sphingomyelin, and cardiolipin. An example of an emulsifier is sorbitan A. Surfactants are usually selected from fatty acids, polyethylene glycol fatty acid esters, polyethoxylated fatty acid esters, polyethoxylated fatty alcohol ethers, alkylene oxide condensations of organic compounds with 1 or more hydroxyl groups thing. The surfactant can be a natural biocompatible surfactant such as lecithin or a pharmaceutically acceptable non-natural surfactant such as Tween-80. Suitable natural ingredients related to lecithin such as EPICURON 120 (Lucas Meyer, Germany), which is a mixture of about 70% phosphatidylcholine, 12% phosphatidylethanolamine and about 15% of other phospholipids; OVOTHIN 160 (LucasMeyer, Germany). Germany), which is a mixture containing about 60% phosphatidylcholine, 18% phosphatidylethanolamine and 12% other phospholipids; a purified phospholipid mixture LIPOID E-75 or LIPOID E80 (lipoid, Germany), It is a phospholipid mixture containing approximately 80% phosphatidylcholine, 8% phosphatidylethanolamine, 3.6% non-polar lipids and approximately 2% sphingomyelin. Purified egg yolk phospholipids, soy phospholipids or other purified mixtures of phospholipids can be used as this ingredient. Listed are representative phospholipids, but are not limited to these phospholipids, and other phospholipids well known to those skilled in the art can also be used. Other examples of surfactants are polyethylene glycol esters of fatty acids, which are of various origins such as castor oil (EMULFOR), polyethoxylated fatty acids such as stearic acid (SIMULSOL M-53); NONIDET; polyethoxylated Polyisooctylphenol/formaldehyde polymer (TYLOXAPOL); polyoxyethylene fatty alcohol ether (BRIJ); polyoxyethylene non-phenyl ether (TRITON N); and polyoxyethylene isooctylphenyl ether (TRITON X), etc. . In some embodiments, emulsions can be formed and stabilized in the substantial absence of one or more co-surfactants selected from non-halogenated aliphatic C3-C6 alcohols, free fatty acids, mono- or diglycerol esters, polyglyceryl fatty acid esters or lysophosphatidylcholine. However, alternative compositions are equally suitable and can be easily prepared by those skilled in the art, for example, containing 5.0% PLURONIC, 10% squalene, 0.4% Tween-80, qs phosphate buffer (pH 7.4) To make the composition, add the ingredients to a test tube and stir to mix until a milky emulsion is obtained. This composition should be prepared or frozen at 4°C prior to administration. For example, Composition 2 contains 5.0% TETRONIC1501, 10% squalane, 0.4% Tween-80, qs phosphate buffered saline (pH 7.4); then solid N-acetylmuramoyl-L -Threonyl-D-isoglutamine (Thr-MDP) to form a "concentrate" at a concentration of 500 μg/mL. This concentrate was then mixed with 2 x antigen solution (hCG in saline, 1 mg/mL) to form the formulation of the present invention. HCG is preferably present at about 0.00001-10%, more preferably at about 0.0001-5%, and most preferably at 0.001-1% by weight of the composition. In addition, the pH should also be in a range suitable for stabilizing hCG. The continuous phase of the composition is an aqueous phase to which are added salts, sugars, antioxidants, preservatives, microbicides, buffers, osmoticants, cryoprotectants and other pharmaceutically useful additives or solutes. Typical preservatives include thimerosal, chlorobutanol and methyl, ethyl, propyl or butyl parabens. Typical tonicity regulators include glycerol and mannitol, with glycerol being preferred. A preferred oil phase antioxidant is alpha-tocopherol or alpha-tocopheryl succinic acid. The aqueous phase may also include an antioxidant of a polyamine carboxylic acid, such as ethylenediaminetetraacetic acid or other pharmaceutically acceptable salts.

Example 2

The instant composition consists of two parts. The first moiety is N-acetylmuramoyl-L-threonyl-D-isoglutamine (Thr-MDP), which is a derivative of a mycobacterial cell wall component. The second part was phosphate buffered saline which included final concentrations of 5% squalane, 1.25% Pluronic and 0.2% Tween 80 (vehicle). For practical purposes, the desired amount of hCG is mixed with the microfluidic vehicle (second part) to obtain a homogeneous emulsion. Then add MDP and shake briefly. The optimal clinical response concentration can be determined by varying the concentration of MDP in the mixture. As an adjuvant control, mice can be infused with soluble hCG mixed with alum or complete Freund's adjuvant (CFA) according to the manufacturer's manual (Pierce chemical, Rockford, III).

Those of ordinary skill in the art will appreciate that such a mouse model indicates that an equivalent experiment or treatment would induce the same clinical response in a human, domesticated or agricultural animal. The formulation and the amount of hCG to produce the desired clinical effect can be determined empirically without undue experimentation by several routine procedures well known to those of ordinary skill in the art. Accordingly, one of ordinary skill in the art would determine the minimum dose of the mixture to be administered to humans, domesticated animals, and agricultural animals if necessary to minimize the therapeutic side effects of the mixture while obtaining an effective response. level, thereby inducing the desired clinical effect. In normal use, such mixtures may be injected according to any of a number of basic procedures, but subcutaneous or intramuscular injections are particularly preferred, at a site where the emulsion remains in a stable form for days or weeks.

Example 3

The hCG aqueous suspension was added to the oil phase at room temperature while homogenizing with a homogenizer. The addition of the aqueous phase was stopped when the ratio of oil to hCG suspension reached 5-6:3-5 parts. Homogenization was continued until the droplet size of the aqueous phase reached approximately 0.05-0.5 μm. The oil phase included the following: 93.6% macro 52; 6.0% sorbitan A or sorbitan 80 or Span 80 (mannide monooleate); 0.4% Tween 80 ( polyoxyethylene 20 sorbitan monooleate). The components of the liquid phase can be heated to 110°C individually in an autoclave or sterile filtered as a mixture. The stability of the emulsion is determined by 2 factors: (1) After emulsification, use a pipette to drop it directly on the water surface so that the droplets will not spread and remain intact; (2) Storage at 37°C for 4 weeks will not form any water Mutually. The final concentration of the emulsion thus prepared contains about 10% by weight of hCG, and the dose used for each subject is 0.5 mL when injected intramuscularly or subcutaneously.

Example 4

Without being limited to the above examples, the composition of the present invention containing dimeric hCG can include two emulsifiers at the same time, thus providing better stability. In this composition, the main emulsifier is selected from polyoxypropylene-polyoxyethylene block copolymer, glycerol monooleate, glycerol dioleate, sorbitan sesquioleate, Brij 93 polyoxyethylene dioleate alcohol, sorbitan monooleate and mixtures thereof, while the second emulsifier is selected from polyoxyethylene fatty acid esters, Pluronic F68, ethylene oxide, lecithin and mixtures thereof. The oil portion of this composition is a triglyceride selected from the group consisting of tricaproylglyceride, tricapryloylglyceride, tripalmitoylglyceride and mixtures thereof. Other suitable oils include vegetable and animal oils. Suitable vegetable oils include: olive oil, safflower oil, sesame oil and soybean oil and suitable animal oils include those containing glycerides. Preferred mineral oils include No. 40 white oil, carnation light oil and Klearol light oil. Mixtures of these oils can also be used.

To prepare the primary emulsion containing mineral oil, about 1 to about 50% by volume, preferably about 2 to about 40% by volume of hCG in water; about 8 to about 58% by volume, preferably about 14 to about 25% by volume of mineral oil; and about 2 to about 30% by volume, preferably about 5 to about 15% by volume of the primary emulsifier mixed together. The HCG aqueous solution is preferably slowly added to the rapidly stirred oil phase, and mixed, such as with a magnetic stirrer, for about 15-60 minutes, preferably about 25-35 minutes. The mixed primary emulsion is then subjected to higher shear emulsification at a shear rate of About 100,000-500,000, preferably about 500,000-1,000,000 shears per second, such as using a microfluidizer. More complete information on microfluidic homogenizers is presented in US Patent No. 4,533,254. Microfluidic homogenizers provide high shear rates for durations as short as fractions of a second without denaturing proteins such as hCG. The primary suspension is then filtered, eg, using a 5 μm hydrophilic polyvinylidene difluoride filter (Duropore, Millipore). Albumin may be added to the hCG solution prior to emulsification in an amount of about 1-5 g%, preferably about 2-3 g%, to help stabilize the multiemulsion size distribution. A primary suspension of hCG in water in mineral oil or solidified oil is suitable for the preparation of the liquid polysuspensions of the invention and should also yield primary suspension droplets with a diameter of less than 5 μm, preferably less than 3 μm.

Example 5

A water-in-oil-in-oil multiple emulsion consisting of 50% v/v outer saline phase and 0.25% interpolymer P123 was prepared. The remaining 50% v/v dispersed in the water-in-oil phase consisted of 72% saline solution, 18% squalene, 2% Span80 and 32mg copolymer L310 and TNP-HEA at a concentration of 0.5mg/0.5mL emulsion. The emulsion contains 1mg/0.5mL of hCG in emulsion. This water-in-oil emulsion appears under the microscope as particles with a diameter of 1.0-20 μm. Other water-in-oil emulsifiers also suitable for this composition are SF1328, Arlacel P135, DC3225C, DC5200, Abil EM-90 and Abil WE-09. Those skilled in the art will recognize that there are several other water-in-oil emulsifiers which can be substituted for the ingredients listed above.

Example 6

Liposomes containing hCG are prepared according to basic methods well known in the art (see eg US Patent No. 6110492). The following ingredients can be used: DLPC dilauroylphosphatidylcholine, DMPC dimyristoylphosphatidylcholine, DPPC dipalmitoylphosphatidylcholine, DSPC distearoylphosphatidylcholine, DOPC dioleoylphosphatidylcholine Base, DLnPc double linolenic acid phosphatidylcholine, DMPG dimyristoylphosphatidylglycerol, CHOL cholesterol, LA lipid A. In a typical formulation, multilamellar liposomes are made from a mixture of DMPC:DMPG:CHOL:LA in a molar ratio of 9:1:7.5:0.011. Lipid A is used as an adjuvant. In a pear-shaped shaker flask, the lipid mixture was rotary evaporated from the chloroform solution to a dry thin layer under vacuum at about 40 °C. To ensure complete removal of the organic solvent, the shake flask was then placed in a desiccator overnight at room temperature on low vacuum (approximately 0.5 mmHg column). After aspiration, the lipids are carefully swelled in deionized sterile pyrogen-free water by swirling. The resulting suspension was frozen at -55°C using a Virtis Unitop800SL Freeze Mobile, then lyophilized at -20°C overnight and kept at 0-10°C the next day. The lyophilized lipid material is then reconstituted to be encapsulated in the presence of the substance, hCG, to obtain hCG-containing multilamellar liposomes. Suitable buffers for reconstitution are phosphate buffered saline (PBS) or Tris-glycine/NaCl buffer. The concentration of liposomal phospholipids in the reconstitution buffer was 10-200 mM. Wash the liposome three times with 0.15M NaCl solution at 10° C. with 27000×g for 10 minutes each time to remove the hCG that is not wrapped into the liposome capsule. To achieve a final concentration of phospholipids of 10-200 mM, suspend the obtained liposomes in 0.15 M NaCl solution or another suitable isotonic buffer. In addition, the elution step can also be omitted, so that hCG not encapsulated in liposomes or encapsulated in liposomes exists in the preparation.

Example 7

This example allows coupling of hCG to MDP. This process requires the quenching of the first reaction with a thiol compound. This reaction was carried out in 2-(N-morpholine)ethanesulfonic acid (MES) (pH 4.5-5.0). MDP (10 mg) lyophilized from water was resuspended in MES (0.5 mL) (pH 4.5-5.0) and combined with EDC (0.5 mg or approximately 2 mM) dissolved in MES (pH 4.5-5.0) , and reacted at room temperature for 15 minutes. 2-Mercaptoethanol (20 mM final concentration) was added to quench EDC and separated by centrifugation. The reaction mixture was washed once with MES, and then resuspended in 0.5 mL of MES (pH 4.5-5.0). hCG dissolved in MES was added to the activated MDP at a molar ratio of approximately 2:1. MES (0.5M, pH 8.5) was added, the pH of the reaction was slowly raised to 8.5 over 15 minutes, and reacted at room temperature for 2 hours. The concentration of hCG added to MDP can be calculated by quantitative analysis of the terminal carboxyl groups of MDP and expressed as mol/mgMDP. The reaction was quenched by the addition of hydroxylamine to a final concentration of 10 mM. The method of quenching the reaction hydrolyzes any unreacted MDP active sites, resulting in regeneration of the original carboxyl groups. Other methods of quenching the reaction involve the addition of 20-50 mM Tris, lysine, glycine or ethanolamine. In addition to hCG, other biological response modifiers such as IL2 are well known to those skilled in the art and can also be used for this purpose. Separation can be achieved by centrifugation, elution and resuspension in the buffer of choice.

Example 8

The compositions of the present invention can also be used as emulsions which, when administered topically, penetrate the skin. A typical topical composition includes the following: 2% glyceryl sorbitan oleostearate (sorbitan 481), 6% polyethoxylated fatty acid (sorbitan 989) , 15% decanyl oleic acid (dioctyl carbonate), 8% branched chain paraffin (iso-hexadecane), 1% microcrystalline paraffin, 1% MDP, 4% glycerin, 0.7% heptahydrate Magnesium sulfate, 0.2% sodium sorbate, 1% hCG, 0.1% diammonium hydrogen citrate, citric acid (adjust pH to 4-5), add deionized water to 100%.

Example 9

Males over 18 years of age and non-pregnant females were selected according to serodiagnosis of HIV infection by Western blot, defining criteria for AIDS, clinical symptoms and CD4 lymphocyte count less than 300 cells/μL within 30 days before the start of the study. Basic clinical and experimental parameters were used to assess efficacy. Clinical parameters included changes in opportunistic infections, changes in body weight, changes in gastrointestinal function, including stool consistency and frequency, changes in energy levels, changes in appetite, changes in physical strength and endurance, and overall changes in quality of life. Experimental parameters include changes in CD4 and CD8 lymphocyte numbers, selective hematology, blood chemistry and urinalysis, and, if available, changes in viral load, which can be detected by PCR to detect viral RNA.

The results of the study showed that, in accordance with the spirit of the present invention, HIV-positive patients experienced clinical improvement, decreased opportunistic infections, increased body weight, and changes in gastrointestinal function, including decreased severe diarrhea, enhanced energy levels, increased appetite, and Increased libido, improved stamina and stamina, and overall improved quality of life. Experimental parameters were also improved, with increased numbers of CD4 and CD8 lymphocytes, hematology, blood chemistry and urinalysis parameters were improved, in addition, virus RNA was detected by PCR, and viral load was found to be reduced, and infectivity was found to be reduced by TCID detection . When HCG preparations are administered, some minor adverse reactions may occur, limited to minor fever, chills, headache and muscle pain.

Example 10

Female mice with a C3H background (H2k/k, Harlan Sprague Dawley) can be used for these studies. Animals were maintained according to the "Guide for the care and use of laboratory animals" (DHHS, NIH) and received food and water ad libitum. The tumor cell line HOPE2 was maintained through serial passages in vitro. Tumors in syngeneic C3H mice were initiated in vitro by subcutaneous injection of 150,000 passage cells. Tumors were tested every two weeks through two vertical orientations. Each treatment group was compared to a control group that received no treatment. Treatment started 10 days after HOPE2 cell inoculation when most tumors were palpable (approximately 50-75 mm ³ ). Treatment was initiated by injecting mice with soluble hCG (by subcutaneous injection, total volume 0.2 mL) with hCG protein in MDP mixture or alum adjuvant. Before inoculation, hCG and MDP were mixed in Hanks balanced salt solution for 60 seconds so that each mouse received the same amount of hCG as a human, ie 2000 or 5000 IU of hCG protein in 0.2 mL. Alum (Pierce Chemical) and hCG were mixed according to the manufacturer's instructions so that each mouse received an equivalent of 5000 IU of hCG in 0.2 mL. In this example, only 5/8 or 4/8 mice injected with a single dose of soluble hCG (2000 IU or 5000 IU, respectively) showed detectable tumors 41 days after tumor cell inoculation. In contrast, all hCG-injected alum mice (8/8) showed actively growing tumors. Furthermore, significant inhibition of tumor growth was only observed in the hCG-injected MDP-treated group compared to the control (untreated) or alum-treated group. No inhibition of tumor growth or increased rate of tumor regression was found in mice receiving a single injection of hCG in alum.

Accordingly, the present invention features pharmaceutical formulations comprising dimeric hCG and muramyl peptides. Additionally, the invention can be characterized as a therapeutic composition comprising: (a) a therapeutically effective amount of dimeric hCG associated with liposomes; and (b) an oil-in-pack containing oil surrounding said liposomes An emulsion of water in an amount sufficient to enhance the therapeutic response relative to the absence of hCG and liposomes in said emulsion. Still further, the present invention provides a method of treating HIV infection in a subject in need thereof, comprising administering to said subject an effective amount of hCG administered with a water-in-oil emulsion relative to said subject. In the absence of said emulsion, said hCG is present in an amount sufficient to increase the clinical response. The present invention also provides a method of treating cancer in a subject in need thereof, comprising administering to said subject an effective amount of hCG, said hCG being administered with a water-in-oil emulsion, and relative to said hCG Where absent from the emulsion, the amount of the emulsion is sufficient to increase the clinical response. The present invention further provides a therapeutic composition comprising a water-in-oil emulsion having a continuous aqueous phase and a discontinuous oil phase and containing at least 0.01% by weight of dimer hCG. The present invention also provides a method for the preparation of a pharmaceutical formulation comprising supplying and mixing an hCG-containing aqueous suspension with at least one oily component and at least one emulsifier in a quantity sufficient to provide The formulation is given as a water-in-oil emulsion. The present invention further provides a therapeutic composition comprising a water-in-oil emulsion and at least one natural or recombinant water-soluble bioactive protein and optionally at least one muramyl peptide. The present invention also provides a kit for on-site preparation of a pharmaceutical composition, said kit comprising: 1) a first container containing an emulsion, wherein said emulsion comprises: squalane or squalane squalene, sorbitan esters, and an aqueous solution, and 2) a second container containing a therapeutically effective amount of dimer hCG, either in aqueous solution or in powder form, wherein the concentration of the ingredients in each container is Optionally, the combination of the components in such two containers will produce a formulation containing said sorbitan ester in an amount of 1-30% and squalane or squalene in an amount of 1-30%. %, the amount of muramyl peptide is 0.0001-30%, and the amount of hCG is 0.01-99%.

Although the present invention has been fully described above in detail and in detail in conjunction with what are presently considered to be the most practical and preferred embodiments, it will be apparent to those skilled in the art that without departing from the invention set forth herein, In the case of principles and concepts, many modifications can be made to it. Accordingly, the proper scope of the present invention should be determined only by the broadest interpretation of the appended claims so as to include all such modifications and all equivalents to that described in the specification.

Claims (33)

1 comprising dimer hCG and muramyl peptide pharmaceutical formulation.

(2) as claimed in claim 1, wherein the composition further comprises an emulsifier.

3 according to claim 2, wherein the composition further comprises a surfactant Agent.

As claimed in claim 3, wherein the composition further comprises an oil.

5 according to claim 1, wherein the composition comprises at least 0.01% by weight of dimeric Body hCG.

6 A therapeutic composition comprising: (a) a therapeutically effective amount of a combination of liposomes Dimer hCG; and (b) surrounding said liposomes contain oil emulsion oil in water, as opposed to hCG and liposomes does not exist in the case of the emulsion, the emulsion present in an amount sufficient to increase Plus therapeutic response.

As claimed in claim 6, wherein the composition, wherein said oil is squalene.

As claimed in claim 6, wherein the composition, wherein said hCG containing at least 0.1% Volume of the oil.

(10) according to claim 6, wherein the composition, wherein said composition further comprises One of the other emulsifiers.

(10) according to claim 6, wherein the composition, wherein said composition further comprises One of the other emulsifiers....

(10) according to claim 6, wherein the composition, wherein said composition further comprises One of the other emulsifiers....

12 according to claim 11, wherein the composition, wherein said adjuvant is selected from N-acetyl- Glucosaminyl-N-acetyl - muramyl-L-alanyl-D-iso-glutamine (GMDP), N-acetylglucosamine Sugar amine (β-1, 4)-N-acetyl - muramyl-L-alanyl-D-iso-glutamine, N-acetyl glucosamine Amino-N-acetyl - muramyl-L-alanyl-D-glutamic acid (GMDP-A), muramyl dipeptide phospholipid Acyl ethanolamine, muramyl tripeptide phosphatidyl ethanolamine, muramyl tripeptide phosphatidyl ethanolamine, CGP11637 (demethyl-MDP), α (N-acetyl - muramyl-L-alanyl-D-iso-glutamine), β, γ-dipalmitoyl-sn-glycerol, α (N-acetyl - muramyl-D-alanyl-D-isoglutaminyl Amines), β, γ-dipalmitoyl-sn-glycerol, α (N-acetyl - muramyl-L-alanyl-D-isoglutaminyl Amide group-L-alanine), β, γ-dipalmitoyl-sn-glycerol, α (N-acetyl - muramyl-D-C Glycyl-D-iso-glutamine yl-L-alanine), β, γ-dipalmitoyl-sn-glycerol, N-acetylmuramic Wall acyl-L-alanyl-D-iso-glutamine yl-L-alanine -2 - (1,2 - dipalmitoyl-sn-glycero-3 - Hydroxyapatite acyloxy) acetamide, glucosaminyl muramyl peptides, murametide, murabutide, muradimetide, myramistin, N-acetyl-muramyl-L-threonyl-D-iso-glutamine, N-acetyl-muramyl-L-α-amino-butyl-D-iso-glutamine ,6-O-stearoyl-N-acetyl-muramyl Acyl-L-α-amino-iso-butyl-D-glutamine, N-acetyl-muramyl-L-valyl-D-isoglutaminyl Acrylamide, N-acetyl-muramyl-L-alanyl-D-iso-glutamine, N-acetyl - demethyl muramyl -L-alanyl-D-iso-glutamine, N-acetyl-muramyl-L-alanyl-D-glutamine butyl Ester, N-acetyl-muramyl-L-seryl-D-iso-glutamine, N-butyl-muramyl-L-α-amino- Iso-butyl-D-glutamine, N-acetyl-muramyl-L-threonyl-D-iso-glutamine, bis (6-O- Muramyl dipeptide) O-palmitoyl alcohol acid, muramyl tripeptide phosphatidyl ethanolamine, N-acetyl- Muramyl-L-alanyl-D-iso glutaminyl-L-alanine -2 - (1,2 - dipalmitoyl-sn-glycerol - 3 - (hydroxy-phosphoryloxy)) acetamide, N-acetyl-muramyl-L-alanyl-D-glutamine butyl ester, N-acetyl-muramyl-L-alanyl-D-iso glutaminyl-L-alanine -2-1,2 - dipalmitoyl-sn- Glycerol-3 - (hydroxy-phosphoryl) ethyl amide (MTP-PE), cholesterol group-MDP, N-acetyl-muramyl Acyl-L-alanyl-D-iso-glutamine butyl β-glucosidase 2 - acetamido-4, 6 - di-O-acetyl- - 2 - deoxy-3-O-[(R) -1 - (methoxycarbonyl) ethyl]-α-D-glucopyranose, (β-Butyl - MDP, MTPO-26, β-cholesteryl-MDP), saponin (Taurosid I), N-acetyl-demethyl Muramyl-LN-methyl-propionyl-D-iso-glutamine octanamide, UDP-N-acetyl-muramyl five Peptides, L4-MDP-ONB, L-alanyl-γ-D-glutamyl - in - diaminopimelic acid, 1,6 - de Water, muramyl dipeptide, N-acetyl glucosaminyl-β-1 ,4-N-acetyl muramyl pentapeptide - pyrophosphoric acid - Ten One terpene alcohol ,3-O-[acetyl-muramyl-D-iso-glutaminyl] -1,2 - dipalmitoyl-sn-glycerol, L- Threonyl-MDP-GDP, L-iso-threonyl-MDP-GDP, trehalose 6,6 - two esters, muramyl Dipeptide, B30 muramyl dipeptide and muramyl dipeptide - lysine. ...

12 according to claim 11, wherein the composition, wherein said adjuvant is selected from N-acetyl- Glucosaminyl-N-acetyl - muramyl-L-alanyl-D-iso-glutamine (GMDP), N-acetylglucosamine Sugar amine (β-1, 4)-N-acetyl - muramyl-L-alanyl-D-iso-glutamine, N-acetyl glucosamine Amino-N-acetyl - muramyl-L-alanyl-D-glutamic acid (GMDP-A), muramyl dipeptide phospholipid Acyl ethanolamine, muramyl tripeptide phosphatidyl ethanolamine, muramyl tripeptide phosphatidyl ethanolamine, CGP11637 (demethyl-MDP), α (N-acetyl - muramyl-L-alanyl-D-iso-glutamine), β, γ-dipalmitoyl-sn-glycerol, α (N-acetyl - muramyl-D-alanyl-D-isoglutaminyl Amines), β, γ-dipalmitoyl-sn-glycerol, α (N-acetyl - muramyl-L-alanyl-D-isoglutaminyl Amide group-L-alanine), β, γ-dipalmitoyl-sn-glycerol, α (N-acetyl - muramyl-D-C Glycyl-D-iso-glutamine yl-L-alanine), β, γ-dipalmitoyl-sn-glycerol, N-acetylmuramic Wall acyl-L-alanyl-D-iso-glutamine yl-L-alanine -2 - (1,2 - dipalmitoyl-sn-glycero-3 - Hydroxyapatite acyloxy) acetamide, glucosaminyl muramyl peptides, murametide, murabutide, muradimetide, myramistin, N-acetyl-muramyl-L-threonyl-D-iso-glutamine, N-acetyl-muramyl-L-α-amino-butyl-D-iso-glutamine ,6-O-stearoyl-N-acetyl-muramyl Acyl-L-α-amino-iso-butyl-D-glutamine, N-acetyl-muramyl-L-valyl-D-isoglutaminyl Acrylamide, N-acetyl-muramyl-L-alanyl-D-iso-glutamine, N-acetyl - demethyl muramyl -L-alanyl-D-iso-glutamine, N-acetyl-muramyl-L-alanyl-D-glutamine butyl Ester, N-acetyl-muramyl-L-seryl-D-iso-glutamine, N-butyl-muramyl-L-α-amino- Iso-butyl-D-glutamine, N-acetyl-muramyl-L-threonyl-D-iso-glutamine, bis (6-O- Muramyl dipeptide) O-palmitoyl alcohol acid, muramyl tripeptide phosphatidyl ethanolamine, N-acetyl- Muramyl-L-alanyl-D-iso glutaminyl-L-alanine -2 - (1,2 - dipalmitoyl-sn-glycerol - 3 - (hydroxy-phosphoryloxy)) acetamide, N-acetyl-muramyl-L-alanyl-D-glutamine butyl ester, N-acetyl-muramyl-L-alanyl-D-iso glutaminyl-L-alanine -2-1,2 - dipalmitoyl-sn- Glycerol-3 - (hydroxy-phosphoryl) ethyl amide (MTP-PE), cholesterol group-MDP, N-acetyl-muramyl Acyl-L-alanyl-D-iso-glutamine butyl β-glucosidase 2 - acetamido-4, 6 - di-O-acetyl- - 2 - deoxy-3-O-[(R) -1 - (methoxycarbonyl) ethyl]-α-D-glucopyranose, (β-Butyl - MDP, MTPO-26, β-cholesteryl-MDP), saponin (Taurosid I), N-acetyl-demethyl Muramyl-LN-methyl-propionyl-D-iso-glutamine octanamide, UDP-N-acetyl-muramyl five Peptides, L4-MDP-ONB, L-alanyl-γ-D-glutamyl - in - diaminopimelic acid, 1,6 - de Water, muramyl dipeptide, N-acetyl glucosaminyl-β-1 ,4-N-acetyl muramyl pentapeptide - pyrophosphoric acid - Ten One terpene alcohol ,3-O-[acetyl-muramyl-D-iso-glutaminyl] -1,2 - dipalmitoyl-sn-glycerol, L- Threonyl-MDP-GDP, L-iso-threonyl-MDP-GDP, trehalose 6,6 - two esters, muramyl Dipeptide, B30 muramyl dipeptide and muramyl dipeptide - lysine. ...

14 as claimed in claim 13, wherein said emulsion further comprises Effective amount of a muramyl peptide of subjects administered amount 1-500μg/kg weight.

15 as claimed in claim 13, wherein said liposome Results hCG and Together and able to offer.

16 A method for treating subjects in need thereof of cancer, comprising administering to said subjects Administering an effective amount of hCG, hCG, and the emulsion of oil in water with the application, and the relative In the absence of hCG in the case of the emulsion, the emulsion present in an amount sufficient to increase Pro Bed reactor.

16 A method for treating subjects in need thereof of cancer, comprising administering to said subjects Administering an effective amount of hCG, hCG, and the emulsion of oil in water with the application, and the relative In the absence of hCG in the case of the emulsion, the emulsion present in an amount sufficient to increase Pro Bed reactor....

16 A method for treating subjects in need thereof of cancer, comprising administering to said subjects Administering an effective amount of hCG, hCG, and the emulsion of oil in water with the application, and the relative In the absence of hCG in the case of the emulsion, the emulsion present in an amount sufficient to increase Pro Bed reactor....

19 as claimed in claim 16, wherein said hCG can be static Pulse, intraperitoneal, intrathecal, intramuscular, subcutaneous, intradermal, sublingual, oral, intranasal, intraocular Or topically. ...

19 as claimed in claim 16, wherein said hCG can be static Pulse, intraperitoneal, intrathecal, intramuscular, subcutaneous, intradermal, sublingual, oral, intranasal, intraocular Or topically. ...

21 according to claim 20, wherein the composition, further comprising a therapeutically effective amount of The muramyl peptides.

22 according to the composition of claim 20, wherein said oil phase comprises mineral oil, Squalene, peanut oil, vegetable oil or silicone oil.

23 according to the composition of claim 20, wherein said emulsion comprising surface Surfactant, said surfactant is selected from sorbitan esters, polyoxyethylene sorbitan mono-, di Or tri-esters, polyoxyethylene fatty acids, polyoxyethylene fatty acid ethers, and combinations of these materials.

A process according to claim 23, wherein the composition, wherein said surfactant package Include polysorbates ("Tween", or sorbitan monooleate), sodium dodecyl sulfate (SDS), Polyethoxylated castor oil ("CREMOPHOR"), NP-40, bromide dimethyl dioctadecyl Ammonium (DDA), linear polyoxypropylene polyoxyethylene (POP-POE) block polymers, parked Luo Shamrock 401, Pu stream Ronnie L62LF, general stream Ronnie L101, general stream Ronnie L64, PEG1000, 1501 Johnny special, special Johnny 150R1, especially Johnny 701, special Johnny 901, special Johnny 1301, Atmos 300, Tween 20, Tween 40, Tween 60, Tween 80, and special Johnny 130R1, Sorbitan esters A, sorbitan esters Span 80 and 80, or mannide monooleate. ...

A process according to claim 23, wherein the composition, wherein said surfactant package Include polysorbates ("Tween", or sorbitan monooleate), sodium dodecyl sulfate (SDS), Polyethoxylated castor oil ("CREMOPHOR"), NP-40, bromide dimethyl dioctadecyl Ammonium (DDA), linear polyoxypropylene polyoxyethylene (POP-POE) block polymers, parked Luo Shamrock 401, Pu stream Ronnie L62LF, general stream Ronnie L101, general stream Ronnie L64, PEG1000, 1501 Johnny special, special Johnny 150R1, especially Johnny 701, special Johnny 901, special Johnny 1301, Atmos 300, Tween 20, Tween 40, Tween 60, Tween 80, and special Johnny 130R1, Sorbitan esters A, sorbitan esters Span 80 and 80, or mannide monooleate. ...

26 A process for preparing a pharmaceutical preparation, said method comprising the supply and with a mixture of hCG And an aqueous suspension of at least one oil component and at least one emulsifier, in an amount sufficient to give the Said formulation provides oil in water emulsions.

27 according to the method of claim 26, further comprising a therapeutically effective amount of the The muramyl peptide added to the oil in water emulsion.

27 according to the method of claim 26, further comprising a therapeutically effective amount of the The muramyl peptide added to the oil in water emulsion....

29. According to claim 28, wherein the therapeutic composition, wherein said bioactive The protein is selected somatotropin, human growth hormone (HGH), bovine growth hormone (BGH or BST), Porcine somatotropin (PGH or PST), epidermal growth factor (FGF), α interferon, α-2a interference Su, α-2b interferon, α-N1 interferon, α-N3 interferon, β interferon, β-1 a1 interference Su; β-1b interferon, γ-1a interferon, γ-1b interferon, ω interferon, τ interferon, Interleukin-1, interleukin-1α, IL-1β, IL-10, white Interleukin-11, interleukin-12, interleukin-12, interleukin 15, white fine Cell interleukin-2, interleukin -3, interleukin-4, interleukin-5, interleukin -7, Interleukin-8, erythropoietin (EPO), parathyroid hormone (PTH), including Selenium protein P, cystatin B, endotoxin neutralizing protein, megakaryocyte Stimulating factor (MGDF), granulocyte-macrophage colony-stimulating factor (GM-CSF), cytokines Sub synthesis inhibitory factor (CSIF), genofibrate, α calcitonin, β calcitonin, tumor necrosis Factor (TNF), lymphocyte migration inhibition factor (LIF), tumor invasion inhibiting factors, anti-make A regulatory protein (TAT's), protease inhibitors, BPC 157, lowering hormone, insulin, Glucagon, gastrin, angiotensin, secretin hormone, prolactin, thyroid-stimulating hormone, Melanocyte-stimulating hormone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid stimulating hormone (TSH), blood Small plate erythropoietin (TPO), luteinizing hormone generation, human menopausal gonadotropin, vascular Vasopressin, oxytocin, protirelin, adrenocorticotropic hormone, SOD, urokinase, dissolved Lysozyme, G-CSF, M-CSF, LIF, inhibin A, inhibin B, activin A, activation Su B, NAP-1, MCP-1, MIP-1α, MIP-1β, MIP-2, SISβ, SISδ, SIS ε, PF4, PBP, γIP-10, MGSA, aFGF, bFGF, KJF, PDGF-A, PDGF-B, PD-ECGF, INS, IGF-I, IGF-II, NGF-β, GRO / MGSA, PF4, PBP / CTAP / βTG, IP-10, KC, 9E3, MCP-1/MCAF, MCAF, ACT-2/PAT 744/G26, LD-78/PAT 464, RANTES, G26, I309, JE, TCA3, B7.1, B7.2, ICAM-1, ICAM-2, LFA-1, LFA-3, CD72, CTAPIII, ENA-78, GRO, I-309, PF-4, LD-78, eosinophil-derived neurotoxin (EDN), Antineoplastic urinary protein (ANUP), ribonuclease and angiostatin and their analogs and variants Body. ...

29. According to claim 28, wherein the therapeutic composition, wherein said bioactive The protein is selected somatotropin, human growth hormone (HGH), bovine growth hormone (BGH or BST), Porcine somatotropin (PGH or PST), epidermal growth factor (FGF), α interferon, α-2a interference Su, α-2b interferon, α-N1 interferon, α-N3 interferon, β interferon, β-1 a1 interference Su; β-1b interferon, γ-1a interferon, γ-1b interferon, ω interferon, τ interferon, Interleukin-1, interleukin-1α, IL-1β, IL-10, white Interleukin-11, interleukin-12, interleukin-12, interleukin 15, white fine Cell interleukin-2, interleukin -3, interleukin-4, interleukin-5, interleukin -7, Interleukin-8, erythropoietin (EPO), parathyroid hormone (PTH), including Selenium protein P, cystatin B, endotoxin neutralizing protein, megakaryocyte Stimulating factor (MGDF), granulocyte-macrophage colony-stimulating factor (GM-CSF), cytokines Sub synthesis inhibitory factor (CSIF), genofibrate, α calcitonin, β calcitonin, tumor necrosis Factor (TNF), lymphocyte migration inhibition factor (LIF), tumor invasion inhibiting factors, anti-make A regulatory protein (TAT's), protease inhibitors, BPC 157, lowering hormone, insulin, Glucagon, gastrin, angiotensin, secretin hormone, prolactin, thyroid-stimulating hormone, Melanocyte-stimulating hormone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid stimulating hormone (TSH), blood Small plate erythropoietin (TPO), luteinizing hormone generation, human menopausal gonadotropin, vascular Vasopressin, oxytocin, protirelin, adrenocorticotropic hormone, SOD, urokinase, dissolved Lysozyme, G-CSF, M-CSF, LIF, inhibin A, inhibin B, activin A, activation Su B, NAP-1, MCP-1, MIP-1α, MIP-1β, MIP-2, SISβ, SISδ, SIS ε, PF4, PBP, γIP-10, MGSA, aFGF, bFGF, KJF, PDGF-A, PDGF-B, PD-ECGF, INS, IGF-I, IGF-II, NGF-β, GRO / MGSA, PF4, PBP / CTAP / βTG, IP-10, KC, 9E3, MCP-1/MCAF, MCAF, ACT-2/PAT 744/G26, LD-78/PAT 464, RANTES, G26, I309, JE, TCA3, B7.1, B7.2, ICAM-1, ICAM-2, LFA-1, LFA-3, CD72, CTAPIII, ENA-78, GRO, I-309, PF-4, LD-78, eosinophil-derived neurotoxin (EDN), Antineoplastic urinary protein (ANUP), ribonuclease and angiostatin and their analogs and variants Body. ...

31 A process for preparing a pharmaceutical composition field kit reagents described PACKER Comprising: 1) a first vessel containing an emulsion wherein the emulsion comprises: squalane or corner Squalene, sorbitan ester and an aqueous solution, and 2) a second container comprising a therapeutically effective The amount of dimer hCG, it is an aqueous solution or powder form, wherein each container Component concentration is selected so that the combination of two components of the container will produce a formulation It contains the amount of sorbitan ester is 1-30%, squalane or squalene in an amount of 1 - 30% of the muramyl peptide in an amount of 0.0001-30%, and hCG in an amount of 0.01-99%. ...

31 A process for preparing a pharmaceutical composition field kit reagents described PACKER Comprising: 1) a first vessel containing an emulsion wherein the emulsion comprises: squalane or corner Squalene, sorbitan ester and an aqueous solution, and 2) a second container comprising a therapeutically effective The amount of dimer hCG, it is an aqueous solution or powder form, wherein each container Component concentration is selected so that the combination of two components of the container will produce a formulation It contains the amount of sorbitan ester is 1-30%, squalane or squalene in an amount of 1 - 30% of the muramyl peptide in an amount of 0.0001-30%, and hCG in an amount of 0.01-99%. ...

33 to claim 31, wherein the kit further comprises a therapeutically effective amount of cells Acyl peptides wall, sealing it in a separate container.