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WO2016124922A1 - Traitement d'affections - Google Patents

Traitement d'affections Download PDF

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Publication number
WO2016124922A1
WO2016124922A1 PCT/GB2016/050249 GB2016050249W WO2016124922A1 WO 2016124922 A1 WO2016124922 A1 WO 2016124922A1 GB 2016050249 W GB2016050249 W GB 2016050249W WO 2016124922 A1 WO2016124922 A1 WO 2016124922A1
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WO
WIPO (PCT)
Prior art keywords
composition
crh
alpha
ulcers
ulcer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2016/050249
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English (en)
Inventor
David John SHOTTON
Deirdre Patricia MCINTOSH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aimsco Ltd
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Aimsco Ltd
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Filing date
Publication date
Application filed by Aimsco Ltd filed Critical Aimsco Ltd
Priority to EP16704045.0A priority Critical patent/EP3253404A1/fr
Publication of WO2016124922A1 publication Critical patent/WO2016124922A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2228—Corticotropin releasing factor [CRF] (Urotensin)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • A61K38/34—Melanocyte stimulating hormone [MSH], e.g. alpha- or beta-melanotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • the present invention relates to compositions, including pharmaceutical compositions, for use in the treatment of medical conditions associated with a persistent inflammatory phase, including ulcers and internal damage to muscle and related (e.g. connective) soft tissue.
  • the invention also relates to methods of treatment of such medical conditions using said compositions.
  • Ulcers particularly leg ulcers, are common in the population in general.
  • the differential diagnoses and frequencies of various types of leg ulcers vary with the population studied.
  • Vascular pathology is associated with the majority of leg ulcers. Almost 70% of leg ulcers have a venous etiology; approximately 20-25% are due to arterial insufficiency; and some of these have a mixed vascular etiology.
  • the remaining leg ulcers have a variety of less common causes, including infection, malignancy, vasculitis and other conditions.
  • Epidemiological data suggest that between 1.5-3.0 per 1000 of the population have active leg ulcers (Scottish Intercollegiate Guidelines Network (SIGN).
  • Sign Guideline 120 Management Of Chronic Venous Leg Ulcers 2010
  • the prevalence increases to 20 per 1000 in people over 80 years-of-age (Royal College of Nursing. The management of patients with venous leg ulcers. Audit protocol. 2000).
  • the total cost to the NHS of treating leg ulcers is estimated to be as high as £600 million a year (Scottish Intercollegiate Guidelines Network (SIGN).
  • Sign Guideline 120 Management Of Chronic Venous Leg Ulcers 2010).
  • VLUs venous leg ulcers
  • the most important risk factors are obesity and immobility (Heit JA, Mohr DN, Silverstein MD, et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism. A population-based cohort study.
  • Venous hypertension causes disturbed microcirculation and pathological changes of the capillaries, which eventually locks the condition in a self-amplifying, detrimental cascade with persistent elevated levels and activities of pro-inflammatory cytokines and proteases preventing progress into a healing phase (Agren et al; Acta Derm Venereol Suppl (Stockh). 2000; 210:3-17).
  • Venous leg ulcers can result from venous hypertension due to valve dysfunction, venous obstruction, and/or failure of calf muscle pump function. They often take a prolonged time to heal, frequently months to more than a year, and they commonly recur. Prevention of recurrence is based on surgery or the lifelong use of compression or support stockings. Patients with venous leg ulcers experience increased stress, together with pain; they may have difficulty coping due to decreased mobility, sleep and social interaction. Clearly, complex clinical management challenges can be expected in treating the population with leg ulcers. Leg ulcers are associated with both a significant quality-of-life impact for patients and their families and a substantial economic impact for the healthcare system.
  • the basic principles of treatment are to remove or treat precipitating cause, for example, surgical intervention, to promote circulation and improve venous return, for example, compression therapy, to promote healing, for example, care, lifestyle changes, symptom management, and to promote preventative care, for example, health education, current treatments for chronic leg ulcers include surgery, sclerotherapy, compressive therapy (conventional therapy), and adjuvant pharmacotherapy such as aspirin and pentoxifylline.
  • neurovascular interventions such as lumbar sympathectomy or spinal cord stimulation; systemic therapy with hyperbaric oxygen or intervenous therapy with agents such as prostaglandins; local mechanical therapy such as negative pressure therapy (NPT), electromagnetic stimulation or enhanced local oxygen therapy; finally, topical therapy with vasoactive growth factors or tissue-engineered skin products (Agren et al; Acta Derm Venereol Suppl (Stockh). 2000; 210:3-17).
  • Compression therapy is the gold-standard treatment for venous ulcers. High- compression bandaging is optimal, but this approach may require modification in patients with diabetes, arthritis, infection, or mild arterial disease (ankle-brachial index [ABI] 0.6-0.8). Compression therapy is the most important element of treatment of venous leg ulcers (Nelson EA and Jones JE 1997 The development, implementation and evaluation of an educational initiative in leg ulcer management. Research and Development Unit, Department of Nursing, University of Liverpool). Research has shown that compression improved healing rates compared to treatments using no compression (Rubin J, Alexander J, Plecha E et al 1990 Unna's boot vs polyurethane foam dressings for the treatment of venous ulceration. A randomized prospective study.
  • Ulcerated skin is sometimes colonised with bacteria that do not appear to impede healing.
  • the purpose of the dressing technique is not to remove bacteria but rather to avoid cross-infection with sources of contamination - for example, other sites of patient or other patients.
  • There is strong evidence that the type of dressing has no effect on ulcer healing. (Scottish Intercollegiate Guidelines Network (SIGN). Sign Guideline 120: Management Of Chronic Venous Leg Ulcers 2010).
  • SIGN Standard Intercollegiate Guidelines Network
  • a recent systematic review (Nelson EA and Jones JE 1997 The development, implementation and evaluation of an educational initiative in leg ulcer management. Research and Development Unit, Department of Nursing, University of Liverpool) has concluded that hydrocolloid dressings confer no benefit over simple, low-adherent dressings.
  • tissue repair begins to take place; new collagen fibres are laid down to effect reconstruction of the damaged site.
  • tissue repair may heal on its own.
  • the inflammatory phase persists for extended periods of time and damage to the site actually increases rather than diminishes. This increased damage is due to continued destruction of normal tissue at the site which hinders the repair process. The result is the development of ulcers which enlarge and become established and which are capable of persisting for months or even years without any significant improvement or healing.
  • the inflammatory phase persists for extended periods of time. Again, damage to the site can increase or simply not heal at a rate that would be expected. The result is the development of a chronic and debilitating loss or diminishment of function of that muscle or related (e.g. connective) tissue.
  • the present invention meets one or more of the above needs by providing a composition comprising CRH, CRH binding protein (CRH-BP), alpha-2 macroglobulin (A2M) and alpha-melanocyte stimulating hormone (alpha-MSH) for use in treatment of a medical condition selected from the list consisting of an ulcer and soft tissue damage.
  • the soft tissue damage may be acute soft tissue damage or chronic soft tissue damage.
  • the acute or chronic soft tissue damage may be an internal injury such as a muscle sprain (i.e. damage to a ligament), a muscle strain (i.e.
  • the composition may be a pharmaceutical composition, i.e. it may comprise one or more pharmaceutically acceptable excipients.
  • the composition or pharmaceutical composition may be derived from caprine serum.
  • the composition or pharmaceutical composition may be derived from hyperimmune serum from a goat which has been immunized with a virus, for example an immunodeficiency virus.
  • the immunodeficiency virus may be HIV or it may be SIV.
  • the immunodeficiency virus may be HIV NIB.
  • the immunodeficiency virus may be in the form of a lysate or a heat-killed virus.
  • the ulcers may be decubitus ulcers (i.e. pressure sores such as bed sores).
  • the ulcers may be venous ulcers.
  • the ulcers may be diabetic ulcers, particularly diabetic leg ulcers or diabetic foot ulcers.
  • the ulcers may be neurotrophic ulcers.
  • the ulcers may be arterial (ischaemic) ulcers.
  • the present inventors have determined a proposed mechanism of action by which the composition acts to treat ulcers. Without being bound by any theory, the present inventors consider that the proposed mechanism of action allows the treatment of soft tissue damage.
  • Soft tissue includes tendons, ligaments, fascia, skin, fibrous tissues, connective tissue, fat, synovial membranes, muscles, nerves and blood vessels.
  • the composition of the invention may be used to treat damage to any of these.
  • the composition of the invention may be used to treat a muscle sprain (i.e. damage to a ligament), a muscle strain (i.e. damage to a tendon) and sports- related muscle injury.
  • treatment is meant amelioration of the condition, whether by removal in whole or in part of all or some of the symptoms or attenuation thereof, such that the patient can report e.g. a lower level of discomfort and pain and enjoy a standard of living that is higher than the level prior to starting treatment.
  • PCT publications WO 2003/004049, WO 2003/064472, WO 2005/056053, WO 2005/097183, WO 2006/021814, WO 2007/077465 and WO 2014/001749 describe therapeutic agents which are based on the above-mentioned caprine serum composition and disclose a number of beneficial effects. The respective content of each of these texts is incorporated in full by specific reference.
  • the reader is referred to them for an understanding of how the therapeutic agent may be prepared.
  • the serum has a beneficial effect on treatment of nerve damage and a number of neural disorders, including amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Alzheimer's disease (AD).
  • ALS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • AD Alzheimer's disease
  • CRF corticotropin releasing hormone
  • the present inventors have now discovered that the serum composition described in the above-mentioned documents is useful in treatment of a number of other conditions, including ulcers as well as acute and chronic soft tissue damage.
  • the present inventors suggest that the invention resides in a bioactive component produced by a molecular cascade in treated patients acting on cells of the immune system.
  • the presence of alpha-MSH in the composition of the invention means that the composition of the invention has the capacity to halt inflammatory processes, thereby accelerating the healing of ulcers and soft tissue damage such as muscle sprain (i.e. damage to a ligament), muscle strain (i.e. damage to a tendon) and sports-related muscle injury.
  • Alpha-melanocyte stimulating hormone (alpha- MSH) is generated as a proteolytic cleavage product from ACTH (1-13), which is in turn a cleavage product of proopiomelanocortin (POMC).
  • POMC proopiomelanocortin
  • the invention is accordingly based on the finding that the caprine serum composition is a potently anti-inflammatory product which has the capacity to switch off the continuing pro-inflammatory processes at the molecular level, thus allowing the injured site to repair itself.
  • the skin and hair follicles are key components of the HPA axis as well as target organs.
  • the skin exhibits a highly organised CRH/POMC system analagous to the HPA axis and is a major stress response system.
  • the present inventors propose that when administered to a patient, the CRH within the composition enhances the production and secretion of the POMC peptides a-MSH, ACTH, and ⁇ -endorphin, especially in keratinocytes, melanocytes, endothelial cells and cutaneous nerves by a multistep process that requires POMC processing by prohormone convertases.
  • the melanocortin (MC) receptors including MC1 which has a high affinity for a-MSH and ACTH is expressed in epidermal and follicular keratinocytes, in epidermal and follicular melanocytes, sebocytes, Langerhan cells, monocytes, macrophages, lymphocytes and dermal fibroblasts.
  • MC-2, which is specific for ACTH is expressed in epidermal melanocytes and adipocytes and MC-5 which shows an affinity for a- MSH and ACTH is present in sweat glands sebocytes and adipocytes
  • composition of the invention triggers a molecular reaction in specific cells of the immune system in treated patients that converts the reactive cells to a quiescent state.
  • the quiescent state in the tissues of the skin rapidly reduces the degree of inflammation and therefore creates an environment conducive to treatment of the persistent inflammatory phase.
  • a POMC peptide is meant any peptide having a corresponding sequence, structure, or function.
  • composition of the invention administered to a patient is believed to result in the production of POMC and at a later stage, the production of alpha MSH due to the molecular cleavage of POMC in the pituitary gland and possibly in the skin.
  • administration is believed to stimulate production of endogenous proopiomelanocortin (POMC) which in turn results in the production of the related component peptides including alpha MSH.
  • POMC proopiomelanocortin
  • 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 ACTH, alpha-MSH and beta- endorphin.
  • Alpha-MSH, adrenocorticotrophin (ACTH), beta and gamma lipotropin (LPH), and beta endorphin are all hormones cleaved from a single large precursor, POMC. It is also believed that the composition of the invention containing POMC and its related peptides may have a self-sustaining effect in the patient, in that administration of an initial amount of the composition of the invention leads to endogenous production of POMC and hence its component peptides in the patient; thus, an initial administration of a low level of POMC may have a significant effect on the patient, including an increase in the levels of POMC peptides.
  • composition of the invention may be prepared by any of the methods disclosed in WO 2003/004049, WO 2003/064472, WO 2005/056053, WO 2005/097183, WO 2006/021814, WO 2007/077465 and WO 2014/001749, each of which is incorporated herein by reference.
  • the composition is derived from hyperimmune serum from an ungulate such as a goat which has been immunized with an immunodeficiency virus.
  • the manufacture method may proactively retain molecules having a size greater than 0.2 microns (or greater than 200 kDa).
  • the method might not include a 0.2 micron pore size filtration step; or might not include any filtration step employing a filter pore size of 0.2 microns or less that removes molecules having a size greater than 0.2 microns (or greater than 200 kDa).
  • the method may proactively retain large molecules (e.g. alpha-2 macroglobulin).
  • the manufacture method may include an optional step of treating the serum prior to aliquoting.
  • a suitable precipitation step may be introduced, such as (conventional) ammonium sulphate precipitation. This may be followed by resuspension of the precipitate in an aqueous solution (e.g. PBS buffer), and dialysis - by way of example, a 10 kDa membrane cut-off diafiltration step may be employed (thereby retaining all molecules having a molecular weight greater than 10 kDa).
  • aqueous solution e.g. PBS buffer
  • dialysis - e.g. 10 kDa membrane cut-off diafiltration step
  • Alternate means known to a person skilled in the art e.g. separation columns, etc. may equally be employed.
  • the manufacture method may include an optional microfiltration step (to remove large macromolecules and any other undesirable large structures) whilst retaining molecules having a size (e.g. average diameter) greater than 0.2 microns (or greater than 200 kDa), which pass through the filter as filtrate.
  • a microfiltration step may be included in combination with or separate from any 'treating of serum' step (described above). If employed, a microfiltration step is performed before any 'aliquoting' step (and after any 'treating of serum' step, if present).
  • molecules having a size greater than 0.3 microns (or greater than 300kDa) are retained (e.g. by employing a 0.3 micron pore size microfilter).
  • An alternative microfiltration step may be employed to retain molecules having a size greater than 0.4 microns (or greater than 400 kDa), or to retain molecules having a size greater than 0.5 microns (or greater than 500 kDa), or to retain molecules having a size greater than 0.6 microns (or greater than 600 kDa), or to retain molecules having a size greater than 0.7 microns (or greater than 700 kDa), or to retain molecules having a size greater than 0.75 microns (or greater than 750 kDa), or to retain molecules having a size greater than 0.8 microns (or greater than 800 kDa), or to retain molecules having a size greater than 0.85 microns (or greater than 850 kDa), or to retain molecules having a size greater than 0.9 microns (or greater than 900 kDa).
  • microfiltration to retain molecules in the filtrate having a molecular weight of more than 800 kDa or more than 850 kDa is desirable.
  • a nanofiltration step may also be employed; the nanofiltration step may remove molecules having a diameter greater than 20 nanometres, or greater than 35 nanometres.
  • the manufacture method may include an aliquoting step in which the serum is aliquoted into vials, optionally with protein concentration adjustment, to provide a single dose amount. At this stage it may be frozen (e.g. at minus 22 degrees C) prior to use. In this regard, prior to use, the aliquoted serum is thawed, followed by prompt administration (e.g. within 6 hours, preferably within 4 hours, preferably within 1 hour, preferably within 5 minutes, preferably within 1 minute) to a patient.
  • prompt administration e.g. within 6 hours, preferably within 4 hours, preferably within 1 hour, preferably within 5 minutes, preferably within 1 minute
  • the composition of the invention may be prepared by a method that comprises: providing isolated blood from an ungulate (e.g. a goat), wherein said ungulate has been immunised with a virus (optionally attenuated or otherwise inactivated), and obtaining serum from the blood (e.g. by centrifugation); treating the serum to separate the CRH and other active components of interest; diafiltration (e.g. using a 10kDa cut off membrane) of the separated serum comprising CRH and other active components of interest, thereby retaining molecules having a molecular weight of at least 10 kDa; wherein all of the above steps are performed under cooled conditions (e.g. less than 22 degrees C, such as less than 10 degrees C, or less than 5 degrees C); whilst ensuring that the serum remains unfrozen following treatment to separate the CRH and other active components.
  • a method that comprises: providing isolated blood from an ungulate (e.g. a goat), wherein said ungulate has been immunised with a virus
  • the virus may be HIV or SIV, which may be HIV N I B; the virus may be in the form of a lysate or a heat-killed virus.
  • “serum” is defined as that component of the blood from which the blood cells have been removed, e.g. by centrifugation.
  • exposure to ambient temperature e.g. room temperature, 22 degrees C
  • cold trays ensuring a maximum temperature of less than 22 degrees C, or less than 10 degrees C, or less than 7 degrees C, or less than 5 degrees C
  • the composition may be kept at a constant temperature below 22 degrees C, e.g. at less than 10 degrees C, or less than 7 degrees C, or less than 5 degrees C.
  • the method is carried out as a continuous process, avoiding any freezing steps prior to storage. For example, no freezing step is employed prior to final aliquoting into vials (optionally with adjustment of protein concentration). In particular, it is preferred that no freezing step is carried out once the serum has been treated to separate the CRH and other components of interest.
  • One or more agitation steps may be carried out during the method; these agitation steps may use cold trays.
  • the manufacture method may comprise a final step (e.g. after any protein concentration adjustment step) of freezing for subsequent storage.
  • a final step e.g. after any protein concentration adjustment step
  • no freezing step is employed prior to protein adjustment, or aliquoting.
  • a pyrogenic material for example, RIBI or Freund's adjuvant
  • RIBI RIBI
  • Freund's adjuvant Another possible factor may be exposure of the animal to daylight, with greater daylight hours (or exposure to daylight equivalent) may increase active component serum levels.
  • composition of the invention may comprise suitable pharmaceutically acceptable carriers comprising excipients and other components which facilitate processing of the active compounds into preparations suitable for pharmaceutical administration.
  • Oral formulations may include 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.
  • Formulation 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 methylceilulose, hydroxypropylmethylcellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen.
  • 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.
  • 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.
  • Formulations for oral use 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.
  • 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.
  • Formulations for parenteral administration include aqueous solutions of active compounds.
  • the composition of the invention may take the form of an aqueous solution, preferably in physiologically compatible buffers such as Hank'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.
  • 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.
  • 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.
  • penetrants appropriate to the particular barrier to be permeated may be used.
  • composition of the present invention can be manufactured substantially in accordance with standard manufacturing procedures known in the art.
  • administration may be in a dosage of between 0.01 and 10 mg (total protein) per kg (patient), for example between 0.01 and 5 mg/kg, between 0.025 and 2 mg/kg, or between 0.05 and 1 mg/kg.
  • a product suitable for administration to patients may have a total protein concentration of approximately 4 mg/ml.
  • Improved patient responses have been observed when a staged dosage regimen is employed, for example, based on initial 0.1 ml administrations, followed by 0.5ml administrations, followed by 1 ml administrations.
  • 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.
  • the treatment may be administered by any effective route, such as by subcutaneous injection, although alternative routes which may be used include intramuscular or intra-lesional injection, oral, aerosol, parenteral, topical or via a suppository.
  • routes which may be used include intramuscular or intra-lesional injection, oral, aerosol, parenteral, topical or via a suppository.
  • Methods of parenteral delivery include topical, intra-arterial, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, or intranasal administration.
  • suitable pharmaceutically acceptable carriers comprising excipients and other components that facilitate the processing of the active compounds into preparations suitable for pharmaceutical administration.
  • the treatment may be administered as a liquid formulation, although other formulations may be used.
  • 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.
  • the invention also provides a method of treating ulcers by administering a caprine serum comprising CRH, CRH binding protein (CRH-BP), alpha-2 macroglobulin (A2M) and alpha-melanocyte stimulating hormone (alpha-MSH) to a patient in need thereof.
  • CRH CRH binding protein
  • A2M alpha-2 macroglobulin
  • alpha-MSH alpha-melanocyte stimulating hormone
  • the invention further provides a method of treating muscle sprains (i.e. damage to ligaments), muscle strains (i.e. damage to tendons), and sports-related muscle injury and soft tissue damage by administering a caprine serum comprising CRH, CRH binding protein (CRH-BP), alpha-2 macroglobulin (A2M) and alpha-melanocyte stimulating hormone (alpha-MSH) to a patient in need thereof.
  • a caprine serum comprising CRH, CRH binding protein (CRH-BP), alpha-2 macroglobulin (A2M) and alpha-melanocyte stimulating hormone (alpha-MSH)
  • Figure 1 illustrates a sample schematic of the normal healing process as described above over time, indicating the sequentially overlapping nature of the healing process.
  • Figure 2 illustrates the effect of treatment with the composition of the invention on levels of a number of components, in terms of a -fold (e.g. 2-fold) increase following administration.
  • Figure 3 illustrates the derived protein cleavage products of POMC and its respective products.
  • the processing of POMC involves glycosylation, acetylation, and extensive proteolytic cleavage at sites shown to contain regions of basic protein sequences.
  • FIG. 4 illustrates that treatment of human peripheral blood cells (PBMCs) induces the production of the anti-inflammatory cytokine IL-10 in the monocyte/macrophage sub-population. All determinations were made in triplicate +/- standard deviations. These data are representative of at least three separate experiments.
  • PBMCs peripheral blood cells
  • Figure 5 illustrates a schematic of a macrophage, setting out the factors involved in activation and inhibition of the inflammatory response.
  • Figure 6 illustrates a proposed mechanism of action for the composition of the invention, including its interaction with a macrophage and the modulation of the inflammatory response.
  • Figure 7 illustrates the results of an open-label cross-over study using the composition of the invention on a patient with a persistent ulcer.
  • Figure 7 A shows the state of the ulcer at the start of the study, following 6 months of conventional treatment.
  • Figure 7B shows the state of the ulcer one month following the start of administration of the composition of the invention.
  • Figure 7 C shows the state of the ulcer two months following the start of administration of the composition of the invention.
  • Figure 7D shows the state of the ulcer three months following the start of administration of the composition of the invention.
  • Figure 8 illustrates the results of an open-label cross-over study using the composition of the invention on a patient with a persistent ulcer.
  • Figure 8A and 8B show the state of the ulcer at the start of the study, following 30 months of conventional treatment.
  • Figures 8C and 8D show the state of the ulcer 4 weeks following the start of administration of the composition of the invention.
  • Example 1 Manufacture of the composition
  • the solution was then subjected to diafiltration against a PBS buffer with a molecular weight cut-off of 10,000 Daltons at 4°C. After diafiltration the product was filtered through a 0.2 micron filter into a sterile container and adjusted to a protein concentration of 4 mg/ml. The solution was put into vials to give single doses of 1 ml, and stored at -15 to -25°C prior to use.
  • PBMCs Human peripheral blood cells
  • T and B lymphocytes were obtained from the volunteers and the T and B lymphocytes, together with the monocytes were separated.
  • PBMCs Human peripheral blood cells
  • Each of these cell types was treated with the composition of the invention and the induction of the antiinflammatory cytokine IL-10 was measured in the cell population.
  • the same measurement was carried out in the cell population which was not exposed to the composition of the invention.
  • the results are shown in Figure 4.
  • the level of the anti-inflammatory cytokine IL-10 induced by the composition alone (listed as "Daval product" in Figure 4) was also measured.
  • the product not only contains low concentrations of CRF, POMC peptides and anti-inflammatory cytokines (IL-10 and TGF-beta) but that it also induces the expression and release of CRF and hence POMC peptides including alpha MSH in the patient, which then transform the patients' immunological profile from a TH-I pro-inflammatory profile to a predominantly TH-2 anti-inflammatory profile.
  • Alpha MSH can transform M1 macrophages (secreting pro-inflammatory cytokines) into M2 macrophages which induce an anti-inflammatory environment, thus treating the persistent inflammatory phase and allowing the initiation of tissue repair.
  • the melanocortin (MC) receptors include MC1 which has a high affinity for a-MSH and ACTH. These are expressed in epidermal and follicular keratinocytes, in epidermal and follicular melanocytes, sebocytes, Langerhan cells, monocytes, macrophages lymphocytes and dermal fibroblasts.
  • MC- 2 which is specific for ACTH, is expressed in epidermal melanocytes and adipocytes
  • MC-5 which shows an affinity for a-MSH and ACTH, is present in sweat glands sebocytes and adipocytes.
  • Alpha-MSH modulates the production and action of pro-inflammatory cytokines by suppressing macrophage innate inflammatory activity via endogenous alpha-MSH (melanocortin) receptors.
  • the key to this anti-inflammatory influence is the inhibition of NF-kappa B.
  • Alpha-MSH inhibits the activation of this nuclear factor through preservation of I kappa B alpha, which binds to NF-kappa B and prevents its migration to the nucleus.
  • the proposed mechanism is shown in Figure 6. This anti-inflammatory activity has led to evaluating the use of the composition of the invention in treatment of conditions such as ulcers, which are associated with a persistent inflammatory phase.
  • the composition of the invention has a role to play in connective tissue repair, and thereby the treatment of e.g. sports injuries.
  • Connective tissue forms a framework upon which epithelial tissue rests and within which nerve tissue and muscle tissue are embedded. Blood vessels and nerves travel through connective tissue and the salient cell types involved in immunological defence are found in this tissue. It functions not only as a mechanical support for other tissues but also as a route of communication and transport among other tissues.
  • connective tissue cells The most common connective tissue cells are fibroblasts, adipocytes, mast cells, macrophages (all resident cells) and lymphocytes monocytes and neutrophils which are immigrant cells. In inflamed tissue, macrophages remove and digest bacterial detritus and unwanted products of normal growth and degeneration and are essential for connective tissue healing.
  • monocytes In a site undergoing a persistent inflammatory phase, monocytes mature into M1 proinflammatory macrophages which prolong tissue damage and the development inflamed tissue which enlarges and become established persisting for months without any significant improvement or healing.
  • the composition of the invention inhibits the stimulation of the M1 macrophage and promotes the differentiation of the M2 macrophage, the macrophage type that secretes a number of factors such as growth factors and other cytokines, especially during the third and fourth post-tissue damage days. These factors attract cells involved in the proliferation stage of healing to the area.
  • Example 3 Open-label crossover study in an ulcerated patient
  • FIG 8C and Figure 8D show the results after four weeks of treatment with the composition of the invention.
  • the ulcer was considerably shallower (less than 5 mm in depth) and the exudate had disappeared.
  • the surrounding skin was no longer oedematus and the margins of the ulcer were clearly defined and shrinking (2 cm by 5.5 cm).
  • composition of the invention will also be suitable for other medical conditions associated with a persistent inflammatory phase, including internal damage to muscle and related (e.g. connective) soft tissue as found in sprains (injury to ligaments), strains (injury to tendons) and sports- related muscle injury.
  • sprains injury to ligaments
  • strains injury to tendons
  • sports-related muscle injury including internal damage to muscle and related (e.g. connective) soft tissue as found in sprains (injury to ligaments), strains (injury to tendons) and sports- related muscle injury.

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Abstract

La présente invention concerne une composition comprenant CRH, une protéine de liaison à CRH (CRH-BP), une alpha -2 macroglobuline (A2M) et l'hormone stimulant les alpha-mélanocytes (alpha-MSH), cette composition étant destinée à être utilisée dans le traitement d'une affection sélectionnée dans la liste constituée d'un ulcère ou d'une lésion des tissus mous.
PCT/GB2016/050249 2015-02-03 2016-02-03 Traitement d'affections Ceased WO2016124922A1 (fr)

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EP16704045.0A EP3253404A1 (fr) 2015-02-03 2016-02-03 Traitement d'affections

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GBGB1501800.5A GB201501800D0 (en) 2015-02-03 2015-02-03 Treatment of medical conditions

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014001749A1 (fr) * 2012-06-25 2014-01-03 Aimsco Limited Formulation comprenant crh et l'alpha-2-immunoglobuline
WO2015097460A1 (fr) * 2013-12-23 2015-07-02 Aimsco Limited Formulation améliorée
WO2015170122A1 (fr) * 2014-05-08 2015-11-12 Aimsco Limited Formulation et méthode de production de celle-ci

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014001749A1 (fr) * 2012-06-25 2014-01-03 Aimsco Limited Formulation comprenant crh et l'alpha-2-immunoglobuline
WO2015097460A1 (fr) * 2013-12-23 2015-07-02 Aimsco Limited Formulation améliorée
WO2015170122A1 (fr) * 2014-05-08 2015-11-12 Aimsco Limited Formulation et méthode de production de celle-ci

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