Calcitonin mimetics for the treatment of diseases and disorders
阅读说明：本技术 用于治疗疾病和病症的降钙素模拟物 (Calcitonin mimetics for the treatment of diseases and disorders ) 是由 K·亨利克森 M·卡尔斯达尔 K·安德烈森 于 2018-03-21 设计创作，主要内容包括：本发明涉及人源化降钙素模拟物及其在治疗糖尿病(I型和/或II型)、过量体重、过量食物消耗、代谢综合征、类风湿性关节炎、非酒精性脂肪性肝炎(NASH)、非酒精性脂肪肝、酒精性脂肪肝病、骨质疏松症或骨关节炎、血糖水平调节不良、对葡萄糖耐量试验反应调节不良或食物摄入调节不良中的用途。(The present invention relates to humanized calcitonin mimetics and their use in the treatment of diabetes (type I and/or type II), excess body weight, excess food consumption, metabolic syndrome, rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease, osteoporosis or osteoarthritis, dysregulation of blood glucose levels, dysregulation of response to a glucose tolerance test, or dysregulation of food intake.)
1. A peptide, wherein the peptide is:
CGNLSTCX1LGRLX2QDX3X4KX5X6TFPX7TDVGANAP(SEQ ID NO：26)
wherein the content of the first and second substances,
X1either M or V
X2T or S
X3Either F or L
X4Either N or H, or a combination thereof,
X5either F or L
X6Q or H
X7Q or K
2. The peptide of claim 1, wherein X2Is T, X3Is L, X4Is N, X5Is F, X6Is H, and/or X7Is K.
3. The peptide of claim 1 or 2, wherein X4Is N, X5Is F, X6Is H.
4. The peptide of claims 1-3, wherein the peptide has at least 65% identity with human calcitonin.
5. The peptide of claim 1, wherein the peptide is selected from one of:
CGNLSTCMLGRLSQDLNKFHTFPKTDVGANAP(SEQ ID NO：12)，
CGNLSTCMLGRLTQDLHKLQTFPKTDVGANAP(SEQ ID NO：18)，
CGNLSTCMLGRLTQDFHKLHTFPKTDVGANAP(SEQ ID NO：20)，
CGNLSTCMLGRLTQDLNKFHTFPKTDVGANAP (SEQ ID NO: 24), or
CGNLSTCMLGRLSQDLNKFHTFPQTDVGANAP(SEQ ID NO 25)。
6. The peptide of any one of the preceding claims, formulated for enteral administration.
7. The peptide of any of the preceding claims, formulated for parenteral administration.
8. The peptide of claim 7, formulated for injection.
9. The peptide of any one of claims 1 to 5, formulated with a carrier for oral administration.
10. The peptide of claim 9, wherein the vector comprises 5-CNAC, SNAD, or SNAC.
11. The peptide of claim 6, wherein the peptide is formulated in a pharmaceutical composition for oral administration comprising coated citric acid particles, and wherein the coated citric acid particles increase the oral bioavailability of the peptide.
12. The peptide according to any one of claims 1 to 5 for use as a medicament.
13. The peptide according to claim 12 for use in the treatment of diabetes (type I and/or type II), overweight, excessive food consumption, metabolic syndrome, rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), non-alcoholic steatohepatitis, alcoholic fatty liver disease, osteoporosis, or osteoarthritis, dysregulation of blood glucose levels, dysregulation of the response to a glucose tolerance test, or dysregulation of food intake.
14. The peptide for use as a medicament according to claim 12 or 13, wherein the peptide is administered in combination with metformin or another insulin sensitiser.
Technical Field
The present invention relates to calcitonin mimetics and extends to their use in the treatment of various diseases and disorders, including but not limited to diabetes (type I and type II), overweight, food overdose and metabolic syndrome, nonalcoholic steatohepatitis (NASH), alcoholic and nonalcoholic steatohepatitis, modulation of blood glucose levels, modulation of response to glucose tolerance tests, modulation of food intake, treatment of osteoporosis, and treatment of osteoarthritis.
Background
There are approximately 2.5 billion diabetics worldwide, and this figure is expected to double in the next 20 years. More than 90% of patients in this population suffer from type 2 diabetes (T2 DM). It is estimated that only 50-60% of people currently have been diagnosed with T2DM or at a stage prior to overt T2 DM.
T2DM is a heterogeneous disease characterized by abnormal carbohydrate and fat metabolism, the cause of T2DM is multifactorial, including genetic and environmental factors that affect β cell function and insulin sensitivity in tissues such as muscle, liver, pancreas and adipose tissue.
The criteria for success of the optimal T2DM intervention is a reduction in blood glucose levels, which can be a chronic reduction in blood glucose levels and an increased ability to tolerate high glucose levels after food intake, described by lower peak glucose levels and faster clearance.
Type I diabetes is characterized by a loss of the ability to produce insulin in response to food intake and therefore is unable to regulate blood glucose to normal physiological levels.
The physical structure of bone may be affected by a variety of factors, including disease and injury. One of the most common bone disorders is osteoporosis, which is characterized by low bone mass and deterioration of bone tissue architecture, resulting in increased bone fragility and susceptibility to bone fractures, particularly in fractures of the hip, spine and wrist. Osteoporosis occurs when there is an imbalance such that the rate of bone resorption exceeds the rate of bone formation. Administration of an effective amount of an antiresorptive agent such as calcitonin has been shown to prevent bone resorption.
Inflammatory or degenerative diseases, including joint diseases such AS Osteoarthritis (OA), Rheumatoid Arthritis (RA) or Juvenile Rheumatoid Arthritis (JRA), including inflammation caused by autoimmune reactions, such AS lupus, Ankylosing Spondylitis (AS) or Multiple Sclerosis (MS), can result in a large loss of mobility due to pain and joint destruction. Cartilage that covers and cushions bones within a joint may degrade over time, thus undesirably allowing direct contact of the two bones, which may limit movement of one bone relative to the other and/or cause damage to one bone by the other during joint movement. Subchondral bone just below the cartilage may also degenerate. The administration of an effective amount of an antiresorptive agent such as calcitonin can prevent bone resorption.
Calcitonin is highly conserved in many species. The full-length natural calcitonin is 32 amino acids in length. An example sequence of natural calcitonin is as follows:
salmon CSNLSTCVLGKLSQELHKLQTYPRTNTGSGTP (SEQ ID NO: 1)
Eel CSNLSTCVLGKLSQELHKLQTYPRTDVGAGTP (SEQ ID NO: 2)
Chicken CASLSTCVLGKLSQELHKLQTYPRTDVGAGTP (SEQ ID NO: 3)
Mouse CGNLSTCMLGTYTQDLNKFHTFPQTSIGVEAP (SEQ ID NO: 4)
Rat CGNLSTCMLGTYTQDLNKFHTFPQTSIGVGAP (SEQ ID NO: 5)
Horse CSNLSTCVLGTYTQDLNKFHTFPQTAIGVGAP (SEQ ID NO: 6)
Dog-1 CSNLSTCVLGTYSKDLNNFHTFSGIGFGAETP (SEQ ID NO: 7)
Dog-2 CSNLSTCVLGTYTQDLNKFHTFPQTAIGVGAP (SEQ ID NO: 8)
Pig CSNLSTCVLSAYWRNLNNFHRFSGMGFGPETP (SEQ ID NO: 9)
Human CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAP (SEQ ID NO: 10)
Synthetic variants of natural calcitonin having modified amino acid sequences, which aim to provide improved properties, are disclosed in WO2013/067357 and WO 2015/071229.
There is a continuing need to develop calcitonin analogs with further improved properties, or at least to provide alternative artificial sequences that improve the properties of naturally occurring calcitonin, particularly in terms of amylin and calcitonin receptor agonism, while eliminating CGRP-receptor agonism, thereby ensuring an optimal in vivo efficacy to safety ratio.
However, a problem with peptide-driven therapeutics is the production of anti-drug antibodies (ADA) in response to host exposure for a given treatment (Wu B et al AAPS J.2016: 11 months; 18 (6): 1335-. The appearance of ADA is more common when peptide therapies derived from other organisms (e.g. salmon calcitonin as a therapeutic agent for various bone related diseases) (Grauer et al, Exp clin Endo Diabetes, 1995) and exantate as a treatment for T2DM (Fineman MS et al, Diabetes Obes metabe, 6 months 2012; 14 (6): 546-54), interfere with the efficacy of a given treatment.
Teleost/avian calcitonin has approximately 50% sequence homology with the endogenous ligand human calcitonin (hCT), and it would therefore be advantageous to increase sequence homology with hCT in an attempt to attenuate ADA production by mimicking endogenous targets while retaining the unique ligand properties of the ferritin/avian calcitonin group.
Summary of The Invention
The present invention now provides calcitonin mimetics which are highly similar (in% identity) to human calcitonin but which surprisingly also exhibit useful therapeutic properties, such as improved appetite suppression. As shown herein, the development of such potent 'humanized' calcitonin mimetics is a far from trivial matter. Table 1 (below) provides the amino acid sequences of calcitonin mimetics developed and tested by the applicant. It was found that humanization of certain residues (i.e., replacement of certain residues with equivalent residues found in human calcitonin) resulted in improved efficacy, while replacement of other residues significantly reduced efficacy.
Although most of the tested peptides produced some degree of appetite suppression within 4 hours, it is highlighted in Table 1 that those peptides (KBP-047[ SEQ ID NO: 12], -053[ SEQ ID NO: 18], -058[ SEQ ID NO: 20], -062[ SEQ ID NO: 24], and-063 [ SEQ ID NO: 25]) produced greater reductions in food intake and were the only peptides shown to produce sustained action within 24 hours.
Accordingly, in a first aspect, the present invention relates to a peptide that is a calcitonin mimetic, wherein the peptide is:
CGNLSTCX1LGRLX2QDX3X4KX5X6TFPX7TDVGANAP(SEQ ID NO：26)
wherein the content of the first and second substances,
X1either M or V
X2T or S
X3Either F or L
X4Either N or H, or a combination thereof,
X5either F or L
X6Q or H
X7Q or K
Preferably, X2Is T, X3Is L, X4Is N, X5Is F, X6Is H, and/or X7Is K.
Preferably, X4Is N, X5Is F, X6Is H.
Preferably, the peptide has an identity with human calcitonin of at least 65%, more preferably at least 70%, most preferably at least 75%.
Preferably, the peptide is selected from one of:
KBP-047CGNLSTCMLGRLSQDLNKFHTFPKTDVGANAP(SEQ ID NO：12)，
KBP-053CGNLSTCMLGRLTQDLHKLQTFPKTDVGANAP(SEQ ID NO：18)，
KBP-058CGNLSTCMLGRLTQDFHKLHTFPKTDVGANAP(SEQ ID NO：20)，
KBP-062: CGNLSTCMLGRLTQDLNKFHTFPKTDVGANAP (SEQ ID NO: 24), or
KBP-063：CGNLSTCMLGRLSQDLNKFHTFPQTDVGANAP(SEQ ID NO：25)。
The peptides of the invention may be acylated or otherwise modified at their N-terminus to reduce the positive charge of the first amino acid, and independently may be amidated at their C-terminus.
The peptides may be formulated for administration as a medicament, and may be formulated for enteral or parenteral administration. Preferred formulations are injectable, preferably for subcutaneous injection, however the peptide may be formulated with a carrier for oral administration and optionally wherein the carrier increases the oral bioavailability of the peptide. Suitable vectors include vectors containing 5-CNAC, SNAD or SNAC.
Optionally, the peptide is formulated in a pharmaceutical composition for oral administration, the pharmaceutical composition comprising coated citric acid particles, and wherein the coated citric acid particles increase the oral bioavailability of the peptide.
The invention includes the peptides of the invention for use as a medicament. The peptides can be used for treating diabetes (type I and/or type II), overweight, excessive food consumption, metabolic syndrome, rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease, osteoporosis, or osteoarthritis, dysregulation of blood glucose levels, dysregulation of glucose tolerance test response, or dysregulation of food intake. In particular, the peptides may be used to reduce undesirably high fasting blood glucose levels or to reduce undesirably high HbAlc or to reduce an undesirably high response to a glucose tolerance test.
In some embodiments, the N-terminal side of the calcitonin mimetics discussed above are modified to reduce the positive charge of the first amino acid.e., acetyl, propionyl, or succinyl groups may be substituted on cysteine-1. alternative methods of reducing positive charge include, but are not limited to, PEG-based PEGylation, or the addition of another amino acid such as glutamic acid or aspartic acid at the N-terminus.
A preferred technique for preparing amidated forms of the calcitonin mimetics of the present disclosure is to react a precursor (having glycine instead of the C-terminal amino group of the desired amidation product) in the presence of peptidylglycine α -amidating monooxygenase according to known techniques, wherein the precursor is converted to the amidated product in reactions described in, for example, US4708934 and EP0308067 and EP 0382403.
The production of amidated products can also be accomplished using the methods and amidating enzymes proposed in the following documents: consalvo et al, US 7445911; miller et al, US 2006/0292672; ray et al, 2002, protein expression and Purification, 26: 249-259; and Mehta, 2004, biopharmm. international, month 7, pages 44-46.
The preparation of the preferred amidated peptides can be carried out by the following procedure: for example, by producing glycine-extended precursors in E.coli as soluble fusion proteins with glutathione-S-transferase, or by direct expression of the precursors according to the technique described in US 6103495. This glycine-extended precursor has the same molecular structure as the desired amidation product, except at the C-terminus (where the product terminates- -X- -NH)2And the precursor terminates-X-gly, X being the C-terminal amino acid residue of the product.) α -amidation enzymes described in the above publications catalyze the conversion of the precursor to the product.
The free acid form of the peptide active agents of the present invention may be produced in a similar manner except that the C-terminal glycine is not included on the "precursor", which is the final peptide product and does not require an amidation step.
Unless otherwise indicated, preferred dosages of the calcitonin mimetics of the present disclosure are the same for therapeutic and prophylactic purposes. The required dosage will be discussed in more detail below and will vary depending on the mode of administration.
Unless otherwise indicated or apparent from the context, dosage herein refers to the weight of the active compound (i.e., calcitonin mimetic) that is not affected or compromised by pharmaceutical excipients, diluents, carriers, or other ingredients, but desirably includes such other ingredients. Any dosage form (capsule, tablet, injection, etc.) commonly used in the pharmaceutical industry for delivery of peptide active agents is suitable for use herein, and the terms "excipient", "diluent" or "carrier" include such inactive ingredients as are commonly included, as well as the active ingredients of such dosage forms in the industry. Preferred oral dosage forms are discussed in more detail below, but should not be construed as a proprietary manner of administering the active agents of the present disclosure.
The calcitonin mimetics of the present disclosure can be administered to a patient to treat a number of diseases or disorders. As used herein, the term "patient" refers to any organism belonging to the kingdom animalia. In one embodiment, the term "patient" refers to a vertebrate, more preferably a mammal, including a human.
Accordingly, the present disclosure includes the use of peptides in methods of treating the following diseases or conditions: type I diabetes, type II diabetes or metabolic syndrome, obesity or appetite suppression, or for reducing insulin resistance, or for reducing undesirable high fasting blood glucose levels, or for reducing undesirable peak serum insulin levels, or for reducing an undesirable large response to a glucose tolerance test, or for treating osteoporosis, or for treating osteoarthritis, or for treating non-alcoholic steatohepatitis (NASH), or for treating alcoholic fatty liver disease.
There are many areas of accepted normal range of body weight measurement in view of a variety of factors such as gender, age, and height. Patients in need of a treatment or prevention regimen as described herein include patients who weigh more than accepted norms or who are at a higher risk of becoming overweight or obese than the general population due to genetic, environmental or other accepted risk factors. In accordance with the present disclosure, it is contemplated that calcitonin mimetics may be useful in the treatment of diabetes, where weight control is one aspect of the treatment.
In one embodiment, the method comprises enterally administering to a patient in need thereof a pharmaceutically effective amount of any of the peptides described herein to treat said disorder.
In one embodiment, the method comprises parenteral administration of any one of the pharmaceutically effective amounts of the peptides described herein to a patient in need thereof to treat the condition. For parenteral administration (including intraperitoneal, subcutaneous, intravenous, intradermal or intramuscular injection), solutions of, for example, the peptides of the invention in sesame or peanut oil or in aqueous propylene glycol solution may be used. The aqueous solution should be suitably buffered (preferably to a pH greater than 8) if necessary, and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous purposes. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. Preparation of all of these solutions under sterile conditions can be readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. For parenteral applications, examples of suitable formulations include solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants, including suppositories. The peptides may be formulated in sterile form in multiple or single doses, for example dispersed in a fluid carrier, such as sterile saline or 5% saline dextrose solution, commonly used with injections.
The method may comprise a preliminary step of determining whether a patient is suffering from the condition, and/or a subsequent step of determining to what extent the treatment is effective to alleviate the condition in the patient, e.g. in each case, performing an oral glucose tolerance test or resting blood glucose level.
To improve the control of the body weight of a patient, to bring about weight loss or to avoid weight gain, the active compound is preferably administered once or more times daily, for example at least twice daily, for example 2-4 times daily. The preparation of the active compound may contain unit doses appropriate to such a regimen. The active compounds may be administered to control the body weight of a patient being treated for diabetes or metabolic syndrome.
Oral enteral formulations are intended for ingestion by swallowing for subsequent release in the intestine below the stomach and thus delivery to the liver through the portal vein, rather than holding the formulation in the mouth to allow transfer to the blood stream by a sublingual or buccal route.
Suitable dosage forms for use in the present disclosure include tablets, mini-tablets, capsules, granules, pills, powders, effervescent solids, and chewable solid formulations. These formulations may comprise gelatin, preferably hydrolyzed gelatin or low molecular weight gelatin. Such formulations may be obtained by freeze-drying a homogeneous aqueous solution comprising a calcitonin mimetic and hydrolysed gelatin or low molecular weight gelatin and further processing the resulting solid material into said oral pharmaceutical formulation, and wherein the gelatin may have an average molecular weight of 1000 to 15000 daltons. Such formulations may include a protective carrier compound, such as 5-CNAC or other compounds disclosed herein.
Although oral preparations such as tablets and capsules are preferred, the composition for use in the present invention may take the form of syrups, elixirs and the like, as well as suppositories and the like. Oral delivery is often the delivery route of choice because it is convenient, relatively easy and often painless, resulting in greater patient compliance relative to other delivery modalities. However, biological, chemical and physical barriers such as varying pH in the gastrointestinal tract, the presence of powerful digestive enzymes and the impermeable gastrointestinal membrane of active agents make oral delivery of calcitonin-like peptides to mammals problematic, e.g., oral delivery of calcitonin is a long-chain polypeptide hormone secreted by mammalian parafollicular cells and by the hyperventilated tracheal glands of birds and fish, initially proven difficult, at least in part, due to insufficient stability of calcitonin in the gastrointestinal tract and the inability of calcitonin to be readily transported through the intestinal wall into the bloodstream.
However, suitable oral formulations are described below.
Treatment of patients
In one embodiment, the calcitonin mimetics of the present disclosure are administered in a sufficient dose to maintain a serum level of the mimetics in the patient of 5 picograms per milliliter to 500 nanograms, preferably 50 picograms per milliliter to 250 nanograms, for example 1 to 100 nanograms per milliliter. Serum levels can be measured by radioimmunoassay techniques known in the art. The attending physician may monitor the patient's response and may then vary the dosage somewhat to account for the individual patient's metabolism and response. Near simultaneous release may best be achieved by administering all of the components of the present disclosure as a single pill or capsule. However, the present disclosure also includes, for example, dividing the desired amount of the calcitonin mimetic into two or more tablets or capsules, which can be administered together such that they together provide the desired amount of all ingredients. As used herein, "pharmaceutical composition" includes, but is not limited to, a complete dose suitable for a particular administration to a patient, whether or not one or more tablets or capsules (or other dosage forms) are recommended in a given administration.
Unigene may be used
In one embodiment, the calcitonin mimetics of the present disclosure are preferably formulated for oral delivery in the manner known in U.S. patent publication No. 2009/0317462.
In one embodiment, the calcitonin mimetics of the present invention can be formulated for enteral administration, particularly oral administration, by mixing with a suitable carrier compound. Suitable carrier compounds include those described in U.S. Pat. No.5,773,647 and U.S. Pat. No.5866536, of which 5-CNAC (N- (5-chlorosalicyloyl) -8-aminocaprylic acid, usually as its disodium salt), is particularly effective. Other preferred carriers or delivery agents are SNAD (sodium salt of 10- (2-hydroxybenzamido) decanoic acid) and SNAC (sodium salt of N- (8- [ 2-hydroxybenzoyl ] amino) octanoic acid). In one embodiment, the pharmaceutical composition of the present disclosure comprises a delivery effective amount of a carrier, e.g., 5-CNAC, i.e., an amount sufficient to deliver the compound to achieve the desired effect. Typically, a carrier such as 5-CNAC is present in an amount of from 2.5% to 99.4% by weight of the total composition, more preferably from 25% to 50% by weight of the total composition.
Furthermore, WO 00/059863 discloses disodium salts of formula I
Wherein the content of the first and second substances,
R1，R2，R3and R4Independently hydrogen, -OH, -NR6R7Halogen, C1-C4Alkyl or C1-C4An alkoxy group;
R5is substituted or unsubstituted C2-C16Alkylene, substituted or unsubstituted C2-C16Alkenylene, substituted or unsubstituted C1-C12Alkyl (arylene), or substituted or unsubstituted aryl (C)1-C12Alkylene groups); r6And R7Independently of one another is hydrogen, oxygen or C1-C4An alkyl group; hydrates and solvates thereof are particularly effective for oral delivery of active agents, such as calcitonin, e.g. salmon calcitonin, which are useful in the present disclosure.
Preferred enteric formulations using optionally micronized 5-CNAC may generally be as described in WO 2005/014031.
The compounds can be formulated for oral administration using the methods used in the Capsitionin product of Bone Medical Limited. These may include processes contained in the axprocess formulation. More particularly, the active ingredient may be encapsulated in an enteric capsule that is capable of withstanding the passage through the stomach. This may contain the active compound and a hydrophilic aromatic alcohol absorption enhancer, as described for example in WO 02/028436. In a known manner, the enteric coating may become permeable in a pH-sensitive manner, for example at a pH of 3 to 7. WO2004/091584 also describes suitable formulation methods using aromatic alcohol absorption enhancers.
The compounds can be formulated using the methods found in the Oramed product, which can include formulations with omega-3 fatty acids, as found in WO2007/029238 or as described in US5,102,666.
In general, pharmaceutically acceptable salts (especially mono-or disodium salts), solvates (e.g., alcohol solvates), and hydrates of these carriers or delivery agents can be used.
Oral administration of a pharmaceutical composition according to the present disclosure may be accomplished periodically, e.g., once or more times per day or week; intermittently, e.g. aperiodically over a day or week; or cyclically, e.g., periodically for days or weeks, followed by a period without administration. The dosage form of the pharmaceutical composition of the disclosed embodiments may be any known form, for example, a liquid or solid dosage form. Liquid dosage forms include solution emulsions, suspensions, syrups and elixirs. In addition to the active compound and a carrier such as 5-CNAC, the liquid formulations may also include inert excipients commonly used in the art, such as solubilizers, e.g., ethanol; oils such as cottonseed, castor, and sesame oils; a wetting agent; an emulsifier; a suspending agent; a sweetener; a seasoning; and solvents such as water. Solid dosage forms include capsules, soft gel capsules, tablets, caplets, powders, granules or other solid oral dosage forms, all of which can be prepared by methods well known in the art. The pharmaceutical composition may additionally comprise additives in commonly used amounts, including but not limited to pH adjusters, preservatives, flavorants, taste masking agents, flavorants, humectants, synergists, colorants, surfactants, plasticizers, lubricants such as magnesium stearate, glidants, compression aids, solubilizers, excipients, diluents such as microcrystalline cellulose, for example Avicel pH 102 supplied by FMC corporation, or any combination thereof. Other additives may include phosphate buffer salts, citric acid, glycols, and other dispersants. The composition may further comprise one or more enzyme inhibitors, such as actinomycin or epirubicin and derivatives thereof; aprotinin, Trasylol and Bowman-Birk inhibitors. In addition, transport inhibitors, i.e., [ rho ] -glycoproteins such as ketoforsine, may be present in the compositions of the present disclosure. The solid pharmaceutical composition of the present invention can be prepared by a conventional method, for example, by mixing, kneading and filling a mixture of the active compound, a carrier such as 5-CNAC and any other ingredient into capsules, or instead of filling into capsules, followed by molding, and then further tableting or compression-molding to obtain tablets. Alternatively, a solid dispersion may be formed by known methods and then further processed to form tablets or capsules. Preferably, the ingredients in the pharmaceutical compositions of the present disclosure are homogeneously or homogeneously mixed throughout the solid dosage form.
Alternatively, the active compound may be formulated as a conjugate with the carrier, which may be an oligomer as described in US2003/0069170, for example
Compound (I)
These conjugates can be administered with fatty acids and bile salts as described therein.
Conjugates with polyethylene glycol (PEG) may be used, as described by mansor et al.
Alternatively, the active compound may be mixed with a nitroso-N-acetyl-D, L-penicillamine (SNAP) and Carbopol solution or taurocholate and Carbopol solution to form a mucoadhesive emulsion.
The active compound can be incorporated into the chitosan nanocapsule as disclosed by Prego et al (optionally as disclosed by Prego C, Torres D, Fernandez-Megia E, Novoa-carbopollal R,
Other suitable strategies for oral formulation include the use of Transient Permeability Enhancer (TPE) systems as described in WO2005/094785 to Chiasma corporation. TPE utilizes an oily suspension of solid hydrophilic particles in a hydrophobic medium to protect drug molecules from inactivation due to the harsh Gastrointestinal (GI) environment and at the same time acts on the GI wall to induce permeation of their cargo drug molecules.
Practical examples of these techniques are also described in Caliceti, P.Salmaso, S., Walker, G. and Bernkop-Schn ü rch, A. (2004) 'Development and inhibition of an oral insulin-PEG delivery system', Eur.J.Pharm.Sci., 22,315, 323; Guggi, D.D., auto, A.H. and Bernkop-Schn ü rch, A. (2003) 'oral dosage delivery system', syste. delivery system: in vivo, Bernkop-Schn 125, Salmon J.J.Patch.J.J.Patch.J.J.Sci.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.S., Walker, G.G.G.G.P.P.P.P.P.P.P.P.P.P.D.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.delivery system, Eur.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P,
As described in WO2004/084870, the active compound may be formulated in seamless microspheres, wherein the active pharmaceutical ingredient is dissolved as an emulsion, microemulsion or suspension formulated as a pellet; and variably coated by conventional or novel coating techniques. The result is an encapsulated drug in a "pre-dissolved" form that, when administered orally, provides a predetermined immediate or sustained release of the active drug to a specific location and at a specific rate along the gastrointestinal tract. In essence, pre-dissolution of the drug enhances the predictability of its kinetic profile, while enhancing permeability and drug stability.
Chitosan coated nanocapsules as described in US2009/0074824 may be used. The active molecules administered with this technique are protected inside nanocapsules because they are stable to the action of gastric juices. Furthermore, the mucoadhesive nature of the system enhances the time of adhesion to the intestinal wall (delayed gastrointestinal transit of these systems has been demonstrated), helping to more efficiently absorb the active molecules.
A method developed by TSR1 corporation may be used. These include the Hydrophilic Solubilization Technique (HST), in which gelatin, a naturally derived collagen extract with positive and negative charges, coats the particles of active ingredient contained in the lecithin micelles and prevents them from aggregating or agglomerating. This results in improved wettability of the hydrophobic drug particles by polar interactions. In addition, amphiphilic lecithin lowers the surface tension between the dissolving fluid and the particle surface.
The active ingredient may be formulated with cucurbituril as an excipient.
Alternatively, the GIPET technology of Merrion Pharmaceuticals can be used to produce enteric coated tablets containing the active ingredient and an absorption enhancer which may be a medium chain fatty acid or a medium chain fatty acid derivative as described in US2007/0238707 or a membrane translocation peptide as described in US 7268214.
Can adopt GIRESTMTechnology consisting of a controlled release dosage form in an inflatable bag, placed in a pharmaceutical capsule for oral administration. After the capsule is dissolved, the gas generating system inflates the pouch in the stomach. In clinical trials, pouches have been demonstrated to remain in the stomach for 16-24 hours.
Alternatively, the active substance may be conjugated with a protective modifier, enabling it to withstand enzymatic degradation in the stomach and promoting its absorption. The active substance may be covalently conjugated with a monodisperse short chain methoxy polyethylene glycol glycolipid derivative which, after purification, is crystallized and lyophilized to a dry active pharmaceutical ingredient. These methods are described in US5438040 and www.biocon.com.
One can also use liver directed vesicles (HDV) for active delivery. HDV may consist of liposomes (diameter. ltoreq.150 nm) encapsulating an active substance, which also contain a hepatocyte targeting molecule in their lipid bilayer. Targeting molecules direct the delivery of encapsulated active to hepatocytes and therefore require relatively small amounts of active to function. Such techniques are further described in US2009/0087479, and in www.diasome.com.
The active substance may be incorporated into a composition which additionally comprises a substantially non-aqueous hydrophilic medium comprising an alcohol and a co-solvent, in combination with a medium chain partial glyceride, optionally in admixture with a long chain PEG substance as described in US2002/0115592 for insulin.
Alternatively, intestinal patches described in the following documents may be used: shen Z, Mitragotri S, pharmres.2002, month 4; 19(4): 391-5 'Intestinal Patches for oral drug delivery'.
As described in us patent No.7189414, the active substance may be incorporated into an erodible matrix formed from a hydrogel blended with a hydrophobic polymer.
Suitable oral dosage levels for the adult to be treated may be from 0.05 to 5mg, preferably from about 0.1 to 2.5 mg.
The frequency of dose treatment for a patient may be 1 to 6 times per day, for example 2 to 4 times per day. Ideally, the treatment will be for an extended period of at least 6 weeks, preferably an extended period of at least 6 months, preferably an extended period of at least one year, and optionally an extended period of lifetime.
Combination therapy of related conditions can be performed using a composition according to the present disclosure and separately administering one or more other therapeutic agents. Alternatively, compositions according to the present disclosure may incorporate one or more other therapeutic agents for co-administration.
Accordingly, combination therapy including co-formulations may be prepared with insulin sensitizers including biguanides such as metformin, buformin and phenformin, TZD's (PPAR) such as balaglitazone, pioglitazone, linaglitazone, rosiglitazone and troglitazone, dual PPAR agonists such as azaglitazone, moglutazole and tixaglitazone, or secretagogues including sulfonylureas such as carposamide, chlorpromazine, gliclazide, tosylamide, ralfate, glipizide, glyburide, glibenclamide, gliquidone, glipizide and glimepiride, glimepiride/ubnidazole (K +), such as nateglinide, repaglinide and mitidine, GLP-1 analogs such as exenatide, linagliptin and alistin, DPP, such as gliclazide-4, insulin inhibitors such as insulin-2, insulin analogs including insulin-norgliclazide, insulin analogs such as valgliclazide, insulin-insulin analogs, insulin analogs such as valgliclazide, insulin-insulin analogs, insulin-insulin analogs such as valgliclazide and valglipizide, and valglimepiridine, and other insulin analogs including insulin analogs such as valprozin-2, valgliclazide, and valgliclazide.
Further combinations include co-administration or co-formulation with leptin. Leptin resistance is a recognized component in type 2 diabetes; however, to date, the injection of leptin has not improved in such situations. In contrast, there is evidence that molecules that support amylin and thus amylin-like ability, such as salmon calcitonin mimetics, are capable of improving leptin sensitivity. The amylin/leptin combination shows a synergistic effect on body weight and food intake as well as insulin resistance [ Kusakabe T et al ].
Drawings
FIG. 1 β -arrestin recruitment dose response as a function of calcitonin receptor activation for KBP-046-KBP-054 (FIG. 1A) and KBP-058-KBP-063 (FIG. 1B) doses ranged from 1. mu.M to 15pM, data shown as vector folding, screening was performed in DiscovexX U20S CALCR Pathhonter cells.
FIG. 2 β -inhibitor recruitment dose response of KBP-046-KBP-054 (FIG. 2A) and KBP-058-KBP-063 (FIG. 2B) as a function of amylin receptor activation the dose ranged from 1. mu.M to 15pM, data shown as vector folding, screening in CHO-K1 CALCR RAMP3 Pathhonter cells of DiscovexX.
Figure 3 long-term β -arrestin recruitment of KBP-046-KBP-054 (figure 3A) and KBP-058-KBP-063 (figure 3B) and human calcitonin as a function of calcitonin receptor activation single dose at t 0 was 100nM, and 3,6, 24, 48 and 72 hours after initial treatment β -arrestin recruitment was assessed to investigate the extension potential of each ligand data is shown as vector folding.
FIG. 4: KBP-046-KBP-054 (FIG. 4A) and KBP-058-KBP-063 (FIG. 4B) show a sustained reduction in food intake in SD rats. After a single s.c dose of 2.5 μ g/kg KBP, food intake was monitored at intervals of 0-4h and 4-24h to assess the prolongation of the individual KBP. Each rat was individually housed in a single cage, with n-4 per group.
Detailed Description
Examples
The presently disclosed embodiments are described in the following examples, which are presented to aid in understanding the disclosure, and should not be construed to limit in any way the scope of the disclosure as defined in the claims that follow thereafter. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the embodiments, and are not intended to limit the scope of the disclosure nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.
In the following examples, the following materials and methods were used.
The following cell lines expressing calcitonin, amylin, and CGRP receptor were purchased and cultured according to the manufacturer's instructions.
1. Calcitonin receptor (CTR): U20S-CALCR from DiscoveRx (Cat. No: 93-0566C 3).
2. Amylin receptor (AMY-R): CHO-K1 CALCR + RAMP3 from DiscovexX (Cat. No.: 93-0268C 2).
In independent bioassays, CTR and AMY-R cells were treated at the indicated time points and the KBP doses identified in table 1 were increased (1000,250,62.5,15.6,3.9,1.0,0.24,0.06,0.02nM and vehicle).
- 上一篇：一种医用注射器针头装配设备
- 下一篇：基于多聚体IL-15的分子