WO2006117573A1

WO2006117573A1 - Combination therapy

Info

Publication number: WO2006117573A1
Application number: PCT/GB2006/050090
Authority: WO
Inventors: Deirdre Mcintosh
Original assignee: Aimsco Limited
Priority date: 2005-05-04
Filing date: 2006-05-03
Publication date: 2006-11-09
Also published as: GB0509052D0

Abstract

The present invention describes a pharmaceutical composition comprising the opioid receptor antagonist naltrexone, and a) a serum composition obtained from a mamma!, preferably a goat, after challenge with an immunogen; or b) a serum composition obtained from a naÊve mammal, preferably a goat; or c) a POMC peptide; or d) a CRF peptide. The composition is useful for the treatment of diseases such as HIV, certain cancers, and multiple sclerosis, among others. Methods of treatment of such diseases are also described.

Description

Combination therapy

FIELD OF THE INVENTION

The present invention relates to a combination therapy for treatment of, inter alia, multiple sclerosis. The therapy may also be used to treat other disorders.

BACKGROUND TO THE INVENTION Naltrexone

The drug Naltrexone (17-(cyclopropylmethyl)-4,5α-epoxy-3,14- dihydroxymorphinan-6-one) is an opioid receptor antagonist, and was approved by the FDA in 1984 in a 50mg dose for the purpose of helping heroin or opium addicts, by blocking the effect of such drugs. By blocking opioid receptors, naltrexone also blocks the reception of the opioid hormones that the brain and adrenal glands produce: beta-endorphin and met-enkephalin. Many organs in the body have receptors for these endorphins and enkephalins, including virtually every cell of the body's immune system.

Low dose naltrexone (LDN) has been found to be effective in treatment of a range of disorders, including cancers, multiple sclerosis, autoimmune diseases, and HIV. LDN has been indicated as a treatment for the following cancers: Breast Cancer; Carcinoid; Colon & Rectal Cancer; Glioblastoma; Liver Cancer; Lung Cancer (Non-Small Cell); Lymphocytic Leukemia; Lymphoma (Hodgkin's and Non-Hodgkin's); Malignant Melanoma; Multiple Myeloma; Neuroblastoma; Ovarian Cancer; Pancreatic Cancer; Prostate Cancer (untreated); Renal Cell Carcinoma; Throat Cancer; Uterine Cancer. LDN may also be used for treatment of other diseases including ALS (Lou Gehrig's Disease); Alzheimer's Disease; Behcet's Disease; Celiac Disease; Chronic Fatigue Syndrome; Crohn's Disease; Emphysema (COPD); Fibromyalgia; HIV/AIDS; Irritable Bowel Syndrome (IBS); Multiple Sclerosis (MS); Parkinson's Disease; Pemphigoid; Primary Lateral Sclerosis (PLS); Psoriasis; Rheumatoid Arthritis; Sarcoidosis; Systemic Lupus (SLE); Ulcerative Colitis; Wegener's Granulomatosis

The therapeutic dosage range for LDN is from 1.75mg to 4.5mg every night. Dosages below this range are likely to have no effect at all, and dosages above this range are likely to block endorphins for too long a period of time and interfere with their effectiveness.

For the treatment of multiple sclerosis (MS) and a wide range of other diseases, the usual adult dosage is 4.5mg taken orally (in tablet form) once daily, usually at night. People who have multiple sclerosis that has led to muscle spasms are advised to use only 3mg daily and to maintain that dosage.

Goat serum product

PCT publications WO03/004049 and WO03/064472 describe therapeutic agents and treatments which are based on a serum composition with many surprising beneficial effects. The respective content of each of these two texts is incorporated in full by specific reference. In particular, the reader is referred to them for an understanding of how the therapeutic agent can be prepared, and for the indications which can be treated.

Typically a goat is immunised with HIV-3B viral lysate raised in H9 cells. The resulting serum is believed to be active against, among other disorders, multiple sclerosis. The reader is further referred in particular to the section on pages 3 and 4 of WO03/004049 headed Εxample of Production of Goat Serum' for further details of the production of serum. This section is incorporated herein by reference.

These earlier publications describe methods of preparing the serum, and describe a range of immunogens which may be used to cause the serum to have the desired properties. In particular, HIV viral particles, or H9 or PBMC cells or cell lysates are said to be useful in obtaining an active serum. We also believe that at least some beneficial activity may be found in serum obtained from non-immunised animals.

It is believed that activity of the serum may be enhanced by administration of a suitable adjuvant to the mammal. Examples of possible adjuvants may include Freund's complete or incomplete adjuvant; Montanide's ISA adjuvant; Ribi's adjuvants; aluminium salt adjuvants; and nitrocellulose adsorbed protein. The skilled person will be aware of other suitable adjuvants which may be used. It is believed that administration of an adjuvant enhances production of immune system components which provide at least some of the activity of the serum.

Although it is believed that serum obtained from goats is the most effective, sufficient activity may be found in serum obtained from other mammals, particularly ungulates, and purified in the same manner. Ungulates include artiodactyls, such as cattle, sheep, goats, pigs, camels and antelopes; and perissodactyls, for example horses.

International patent application PCT/GB2005/050108, the contents of which are incorporated by reference, describes in more detail the active components of the serum composition, In particular, the active components are believed to include a corticotropin releasing factor (CRF) peptide, and/or proopiomelanocortin (POMC) and its related component peptides, By "a CRF peptide" is meant any peptide having a corresponding sequence, structure, or function to CRF. It will be apparent to the skilled person that the canonical nucleotide and/or amino acid sequences given for human CRF in GENBANK entry BCOl 1031 may be varied to a certain degree without affecting the structure or function of the peptide. In particular, allelic variants and functional mutants are included within this definition. Mutants may include conservative amino acid substitutions; and fragments and derivatives of CRF.

POMC is a peptide (prohormone) produced in the pituitary gland (as well as a number of other organs, certain tumours such as melanomas, and normal skin cells) which is the precursor of a set of corticotrophic hormones which exert a number of effects on the host. POMC is the precursor to alpha, beta, and gamma melanocyte stimulating hormone (MSH); adrenocorticotrophin (ACTH); beta and gamma lipotropin (LPH); and beta endorphin. All of these hormones are cleaved from a single large precursor, POMC, and are termed herein "POMC products".

SUMMARY OF THE INVENTION

It is believed that a combination of the abovementioned serum product and naltrexone or another opioid receptor antagonist is useful in the treatment of various diseases.

According to the present invention, then, there is provided a pharmaceutical composition comprising an opioid receptor antagonist and a serum composition obtained from an ungulate, preferably a goat, after challenge with an immunogen. Also provided is a pharmaceutical composition comprising an opioid receptor antagonist and a POMC peptide; the invention also provides a pharmaceutical composition comprising an opioid receptor antagonist and a CRF peptide. Aspects of the invention also provide a pharmaceutical composition comprising an opioid receptor antagonist and a serum composition obtained from a naϊve ungulate, preferably a goat. A naϊve ungulate or goat is one which has not been pre-immunised with a specific immunogen. It is accepted that a normal goat may well have been previously exposed to environmental immunogens, and such goats may be used in preparation of the compositions of the present invention. For example, the naϊve goat may be a conventional farm goat, and preferably a farm goat which has not been immunized. It is preferred that the goat has not previously encountered any immunogens.

Preferably the opioid receptor antagonist is naltrexone, or a pharmaceutically acceptable salt thereof.

The composition may also comprise one or more peptide regulatory or releasing factors, which may induce a cascade of release of further peptides by a variety of cells in the patient. Suitable factors include α-HLA, TGF-β, and IL-IO, among others.

In preferred embodiments, the composition may comprise one or more of vasopressin, beta endorphin, and leu or met enkephalin. In certain embodiments, the composition may comprise CRF binding protein, CRF-BP. This binds CRF and may act as a reservoir for subsequent release of CRF to the patient.

Administration of pharmaceutical compositions of the invention may be accomplished orally or parenterally. Methods of parenteral delivery include topical, intra-arterial, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, or intranasal administration. In addition to the active ingredients, such compositions may comprise suitable pharmaceutically acceptable carriers comprising excipients and other components which facilitate processing of the active compounds into preparations suitable for pharmaceutical administration.

Pharmaceutical compositions for oral administration can be formulated using pharmaceutically acceptable carriers known in the art in dosages suitable for oral administration. Such carriers enable the compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like suitable for ingestion by the subject.

Pharmaceutical preparations for oral use can be obtained through combination of active compounds with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds if desired to obtain tablets or dragee cores. Suitable excipients include carbohydrate or protein fillers such as sugars, including lactose, sucrose, mannitol, sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methylceiluiose, hydroxypropylmethylcellulose, or sodium carboxymethylceHulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilising agents may be added, such as cross linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof.

Dragee cores can be provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterise the quantity of active compound.

Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain active ingredients mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally stabilisers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilisers. Pharmaceutical formulations for parenteral administration include aqueous solutions of active compounds. For injection, the pharmaceutical compositions of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiologically buffered saline. Aqueous suspension injections can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Additionally, suspensions of the active compounds can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Optionally, the suspension can also contain suitable stabilisers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

For topical or nasal administration, penetrants appropriate to the particular barrier to be permeated may be used in the formulation.

The pharmaceutical compositions of the present invention can be manufactured substantially in accordance with standard manufacturing procedures known in the art.

The invention also provides an opioid receptor antagonist and a serum composition obtained from an ungulate, preferably a goat after challenge with an immunogen, for use as a medicament. Also provided is an opioid receptor antagonist and a POMC peptide, for use as a medicament; the invention also provides an opioid receptor antagonist and a CRF peptide, for use as a medicament. Aspects of the invention also provide an opioid receptor antagonist and a serum composition obtained from a naϊve ungulate, preferably a goat, for use as a medicament. A method of treatment of a disorder may comprise administering an opioid receptor antagonist and a serum composition obtained from an ungulate, preferably a goat after challenge with an immunogen; or an opioid receptor antagonist and a POMC peptide; or an opioid receptor antagonist and a CRF peptide; or an opioid receptor antagonist and a serum composition obtained from a naive ungulate, preferably a goat.

The two components may be administered sequentially or simultaneously; and may be administered as separate medicaments, or as a combined medicament.

The disorder may be selected from an autoimmune disorder, cancers, and HIV. Alternatively, the disorder may be selected from multiple sclerosis; rheumatoid arthritis; optic neuritis; motor neurone disease; autoimmune diseases including lupus, psoriasis, eczema, thyroiditis, and polymyositis; axonal or nerve damage; cancers, in particular myelomas, melanomas, and lymphomas; neural disorders, both demyelinating and non-demyelinating; inflammatory conditions; obesity; nerve conduction disorders; and sexual dysfunction, in particular erectile dysfunction. Other disorders which may be treated include Krabbes disease, Charcot-Marie-Tooth disease, and chronic inflammatory demyelinating polyneuropathy. Alternatively, the disorder may be selected from any of the conditions recited above for which LDN is noted as being useful.

The precise dosage to be administered may be varied depending on such factors as the age, sex and weight of the patient, the method and formulation of administration, as well as the nature and severity of the disorder to be treated. Other factors such as diet, time of administration, condition of the patient, drug combinations, and reaction sensitivity may be taken into account. An effective treatment regimen may be determined by the clinician responsible for the treatment. One or more administrations may be given, and typically the benefits are observed after a series of at least three, five, or more administrations. Repeated administration may be desirable to maintain the beneficial effects of the composition, Typically the dosage may include 1.75 - 4 mg of naltrexone or other opioid antagonist, and i - 50 mg, or 1 - 25 mg, or 1 - 15 mg or 1 - 10 mg or 1 - 5 mg of serum composition, or POMC peptide, or CRF peptide.

The treatment may be administered by any effective route, preferably by subcutaneous injection, although alternative routes which may be used include intramuscular or intralesional injection, oral, aerosol, parenteral, or topical.

The treatment is preferably administered as a liquid formulation, although other formulations may be used. For example, the treatment may be mixed with suitable pharmaceutically acceptable carriers, and may be formulated as solids (tablets, pills, capsules, granules, etc) in a suitable composition for oral, topical or parenteral administration.

DETAILED DESCRIPTION OF THE INVENTION

Preparation of serum composition

Approximately 400 ml of blood is taken from a goat under sterile technique, The animal may typically be re-bled in 10 to 14 days, once the volume of blood is replenished. The blood is then centrifuged to separate the serum, and the serum filtered to remove large clots and particulate matter. The serum is then treated with supersaturated ammonium sulphate (47% solution at room temperature) to precipitate antibodies and other material. The resulting solution is centrifuged at 35000 rpm for 45 minutes at 4°C, after which the supernatant is removed. The precipitated immunoglobulin and other solid material are resuspended in 47% ammonium sulphate/PBS and re-centrifuged as before. The supernatant is discarded and the resulting precipitate is re-dissolved in PBS buffer (phosphate buffered saline) sufficient to redissolve the precipitate. The solution is then dialysed at 4°C through a membrane with a molecular weight cut-off of 10,000 Daltons. Dialysis is carried out in PBS buffer, changed every 4 hours over a period of 24 hours, at 4°C. After 12 hours of dialysis, the contents of the dialysis bag are emptied into a sterile container. The solution is adjusted to 5 mg/ml using PBS, and the resulting solution filtered through a 0.2 micron filter into a sterile container. After filtration the solution is divided into aliquots to give single doses of ImI, and stored at -15 - 25⁰C prior to use.

This solution comprises POMC peptides and CRF peptides. To this may be added a suitable dose of naltrexone, which may then be administered to a patient as appropriate.

Claims

CLAIMS:

1. A pharmaceutical composition comprising an opioid receptor antagonist and a serum composition obtained from a mammal after challenge with an immunogen.

2. A pharmaceutical composition comprising an opioid receptor antagonist and a serum composition obtained from a naive mammal.

3. The composition of claim 1 or 2 wherein the mammal is an ungulate.

4. The composition of claim 3 wherein the ungulate is a goat.

5. A pharmaceutical composition comprising an opioid receptor antagonist and a POMC peptide.

6. A pharmaceutical composition comprising an opioid receptor antagonist and a CRF peptide.

7. The composition of any preceding claim, wherein the opioid receptor antagonist is naltrexone, or a pharmaceutically acceptable salt thereof.

8. The composition of any preceding claim further comprising one or more peptide regulatory or releasing factors.

9. The composition of any preceding claim further comprising one or more of vasopressin, beta endorphin, and leu or met enkephalin.

10. The composition of any preceding claim further comprising CRF binding protein, CRF-BP.

11. An opioid receptor antagonist and a serum composition obtained from a mammal after challenge with an immunogen, for use as a medicament.

12. An opioid receptor antagonist and a serum composition obtained from a naive mammal for use as a medicament.

13. The medicament of claim 11 or 12, wherein the mammal is an ungulate.

14. The medicament of claim 13 wherein the ungulate is a goat.

15. An opioid receptor antagonist and a POMC peptide, for use as a medicament.

16. An opioid receptor antagonist and a CRF peptide, for use as a medicament.

17. A method of treatment of a disorder comprising administering an opioid receptor antagonist and one or more of a) a serum composition obtained from a mammal after challenge with an immunogen; b) a serum composition obtained from a naϊve mammal; c) a POMC peptide; or d) a CRF peptide.

18. The method of claim 17 wherein the mammal is an ungulate.

19. The method of claim 18 wherein the ungulate is a goat

20. The method of any of claims 17 to 19 wherein the disorder is selected from an autoimmune disorder, cancers, and HIV.

21. The method of any of claims 17 to 19 wherein the disorder is selected from multiple sclerosis; rheumatoid arthritis; optic neuritis; motor neurone disease; autoimmune diseases including lupus, psoriasis, eczema, thyroiditis, and polymyositis; axonal or nerve damage; cancers, in particular myelomas, melanomas, and lymphomas; neural disorders, both demyelinating and non- demyeϋnating; inflammatory conditions; obesity; nerve conduction disorders; and sexual dysfunction, in particular erectile dysfunction.

22. The method of any of claims 17 to 19 wherein the disorder is selected from Krabbes disease, Charcot-Marie-Tooth disease, and chronic inflammatory demyelinating polyneuropathy.