WO2012090224A1 - Nouveaux co-cristaux/ sels moléculaires de mésalamine s'utilisant comme médicament anti-inflammatoire amélioré - Google Patents

Nouveaux co-cristaux/ sels moléculaires de mésalamine s'utilisant comme médicament anti-inflammatoire amélioré Download PDF

Info

Publication number
WO2012090224A1
WO2012090224A1 PCT/IN2011/000902 IN2011000902W WO2012090224A1 WO 2012090224 A1 WO2012090224 A1 WO 2012090224A1 IN 2011000902 W IN2011000902 W IN 2011000902W WO 2012090224 A1 WO2012090224 A1 WO 2012090224A1
Authority
WO
WIPO (PCT)
Prior art keywords
mesalamine
glutamine
pharmaceutical
pharmaceutically acceptable
novel
Prior art date
Application number
PCT/IN2011/000902
Other languages
English (en)
Inventor
Rambabu Dandela
Jaggavarapu Satyanarayana Reddy
Ganesh Saraswatula Viswanadha
Ravikumar Nagalapalli
Anand Kamalakaran SOLOMON
Gopikrishna GADDAMANUGU
Anil Kumar Kruthiventi
Original Assignee
Nutracryst Therapeutics Private Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Nutracryst Therapeutics Private Limited filed Critical Nutracryst Therapeutics Private Limited
Publication of WO2012090224A1 publication Critical patent/WO2012090224A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/606—Salicylic acid; Derivatives thereof having amino groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to synergistic pharmaceutical co-crystals/salts comprising Mesalamine as active ingredient in combination with amino acids, nutraceuticals or flavonoids.
  • Mesalazine also known as Mesalamine or 5-aminosalicylic acid (5-ASA), is an antiinflammatory drug used to treat inflammation of the digestive tract, ulcerative colitis and mild-to-moderate Crohn's disease.
  • Mesalazine is a bowel-specific aminosalicylate drug that acts locally in the gut and has its predominant actions there, thereby having few systemic side effects. The common side effects are: (a) Diarrhea, (b) Nausea, (c) Cramping & (d) Flatulence.
  • Mesalamine occurs as white to slightly grey crystals or a light tan to pink crystalline powder and has a solubility of 1 mg/mL in water at 20°C and also is slightly soluble in alcohol.
  • the drug has pKa of 3, 6, and 13.9.
  • compositions containing 5- amino salicylic acid as active ingredient to treat ulcerative colitis.
  • these compositions are pH dependent and require high dosage.
  • the half-life of 5-ASA is 7 to 9 hours, and consequently 4 to 5 days are required to achieve steady-state plasma concentrations.
  • mesalamine is unstable in the presence of water and light, since oxidation and, to a lesser extent, light-catalyzed degradation of the drug occurs thus affecting its physico chemical properties.
  • Preparation of pharmaceutical co-crystals offers an attractive option because they offer multiple opportunities to modify the chemical and/or physical properties of an active pharmaceutical ingredient (API) without compromising the structural integrity of the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • co crystals are defined as hydrogen bonded complexes between an active pharmaceutical ingredient (API) and a co-former (CCF, benign partner molecule), usually having a fixed API: CCF stoichiometry.
  • the co-crystal formers can be selected from the group consisting of phenolics, flavonoids, monoterpenes, aminoacids, alkaloids, vitamins, neutraceuticals, which works synergistically along with active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the other object of the invention is to prepare mesalamine co-crystal in 1 : 1 combination with coformers selected from amino acids, flavonoids or neutraceuticals.
  • the present invention discloses novel synergistic pharmaceutical co-crystal comprising of Mesalamine as API with alpha amino acids, flavones or nutraceuticals.
  • the inventive co-crystal of Mesalamine can be used in Mesalamine sustained release dosage forms.
  • the word 'Mesalamine' as described herein also encompasses Mesalamine salts including Mesalamine hydrochloride.
  • the invention provides novel pharmaceutical composition comprising mesalamine and amino acid co-crystals in association with one or more pharmaceutical carriers.
  • Alpha amino acids are selected from Leucine, isoleucine, lysine, methionine, phenyl alanine, threonine, tryptophan, valine, alanine, asparagines, aspartic acid, cystenine, glutamic acid, glutamine, L-glutamine, glycine, proline, serine, tyrosine, arginine, and histidine, especially L-glutamine.
  • the invention provides novel pharmaceutical composition comprising mesalamine and flavone co-crystals of the current invention in association with one or more pharmaceutical carriers.
  • the invention provides novel synergistic Mesalamine co-crystals which comprise Mesalamine and flavones belonging to a class of 3-hydroxy flavones such as quercetin.
  • the invention provides novel pharmaceutical composition comprising mesalamine and nutraceuticals co-crystals of the current invention in association with one or more pharmaceutical carriers.
  • the invention provides the mesalamine -amino acid co-crystals, wherein said method comprises grinding of mesalamine free base and amino acid in 1 : 1 ratio in acetonitrile.
  • the invention also provides methods for the treatment of the disorder discussed above.
  • Mesalamine co-crystals and pharmaceutical compositions containing them may, according to the invention, be administered using any amount, any form of pharmaceutical composition and any route of administration effective for the treatment.
  • the pharmaceutical compositions of this invention can be administered by any means that delivers the active pharmaceutical ingredient (s) to the site of the body whereby it can exert a therapeutic effect on the patient.
  • Fig.l shows IR spectra of Mesalamine hydrochloride
  • Fig.2 shows IR spectra of Glutamine
  • Fig.3 shows IR spectra of Mesalamine hydrochloride- Glutamine co-crystal
  • Fig.4 shows the PXRD spectra of Mesalamine hydrochloride
  • Fig.5 shows the PXRD spectra of Glutamine
  • Fig.6 shows the PXRD spectra of Mesalamine hydrochloride- Glutamine co-crystal
  • Fig.7 shows NMR peaks of Mesalamine hydrochloride
  • Fig.8 shows NMR peaks of glutamine
  • Fig .9 shows NMR peaks of Mesalamine hydrochloride- Glutamine co-crystal
  • Fig.10 depicts DSC of Mesalamine hydrochloride
  • Fig.l 1 depicts DSC of Glutamine
  • Fig.12 depicts DSC of Mesalamine hydrochloride- Glutamine co-crystal
  • Fig.13 depicts TGA of Mesalamine hydrochloride
  • Fig.15 depicts TGA of Mesalamine hydrochloride- Glutamine co-crystal
  • the present invention relates to novel synergistic pharmaceutical mesalamine co-crystals with high purity, adequate stability, good flow ability and good dissolution properties that can be used in sustained release dosage forms.
  • 5-aminosalicylic acid is an anti-inflammatory drug used to treat inflammation of the digestive tract, ulcerative colitis and mild-to-moderate Crohn's disease.
  • 5-ASA 5-aminosalicylic acid
  • the present invention discloses novel synergistic pharmaceutical co-crystal comprising of Mesalamine as API with alpha amino acids, flavones or nutraceuticals.
  • the inventive co-crystal of Mesalamine can be used in Mesalamine sustained release dosage forms.
  • One preferable conformer is amino acid.
  • the present invention provides novel pharmaceutical composition comprising Mesalamine and amino acid co-crystals in association with one or more pharmaceutical carriers.
  • the a-amino acids which are naturally occurring biomolecules, apart from being essential building blocks for the proteins, have a wide range of biological action.
  • the amino acids being lipophilic helps Mesalamine in binding with blood plasma protein thereby increasing the plasma protein binding effect of the drug which in turn helps slow release of the drug from the co-crystals in unbound form yet maintaining the equilibrium of the drug levels in the body. They are further classified as essential and non essential amino acids.
  • Types of Non Essential Amino Acids are further classified as essential and non essential amino acids.
  • L-Alanine - acts as a producer of energy and it regulates blood sugar. Also, intervenes in the metabolism of glucose.
  • L-Asparagine - is important in the metabolic process of the nervous system.
  • L-Aspartic Acid - is essential for the transformation of carbohydrates into muscular energy.
  • L-Citruline - immune system stimulator helps in the production of body energy and helps to detoxify the liver from ammonia substance.
  • L-Cysteine - stimulates the growth of hair and protects against the damages that can be caused by alcohol and cigarettes.
  • L-Glutamine - helps the memory, concentration, and the correct functioning of mental activity.
  • L-Glutamic Acid - helps in the production of energy and brain function.
  • L-Glycine - slow the muscle degeneration by supplying addional creatine. It is vital for structuring red blood cells and providing amino acids to the body. Glucose and creatine are 2 essential substances in the production of energy and require glycine in their synthesis process.
  • L-Histidine important in the production of red and white blood cells, and is vital for the formation of body tissues.
  • L-Proline - is important ingredient in the formation of tissues.
  • L-Serine - aid the memory, the nervous system function, and is very important in the production of cell energy.
  • L-Tyrosine - helps in the treatment of insomnia, anxiety and depression, as well as allergies and is very important in the function of the thyroid and hypophysis glands. Deficiency of this amino acid is associated to hyperthyroidism (can cause fatigue).
  • L-Carnitine - helps control weight and body fat, as well as reduce the risk of heart problems. Lysine and vitamin B l and B6 along with iron are needed for the body to produce this amino acid.
  • GABA Gamma- Aminobutyric Acid
  • L-Isoleucine - is needed in regulating sugar and the energy levels, as well as in the formation of hemoglobin. This amino acids is transformed and converted into muscle tissue. Lack of this AA produces a symptom similar to hypoglycemia or low blood sugar. L-Leucine - an important amino acid, which is found in animal and vegetable proteins. It is important for controlling the blood sugar level.
  • L-Lysine - an important for the construction of proteins principally in muscles and bones. Helps the assimilation of calcium, to obtain greater mental concentration and helps to lessen the effects of colds, flu and the herpes virus. It helps in the production of hormones, antibodies, enzymes and also in the formation of collagen. The deficiency of this amino acid produces: fatigue, irritability, anemia, and hair loss.
  • L-Methionine - helps to remove poison wastes from the liver and take part in the formation of the liver and kidney tissues. Help the digestive system, weak muscles, fragile hair, and is beneficial for osteoporosis.
  • L-Phenylalanine - helps against depression, obesity, and loss of memory. It is an important element in the production of collagen, the principal fibrous protein in the body. Due to its action in the central nervous system, these amino acids decrease the pain associated with migraines, menstruation, and arthritis. L-Phenylalanine should not be taken by pregnant women or those who suffer from high blood pressure.
  • L-Tryptophan - helps control hyperactivity in children, alleviate stress, is good for the heart. It helps in weight control and allows the growth of the hormones necessary for the production of Vitamin B6 and Niacin.
  • the brain utilizes this amino acid to produce Seratonina and Melatonina, neurotransmitters necessary for transferring nervous impulses from one cell to another. Lack of them (viz. Serotonine and Melatonine) produces depression, loss of sleep and other mental disorders.
  • L-Threonine - found in the heart, central nervous system and muscles. It is beneficial in the formation of collagen and elastin. Helps the liver and maintain the body's proteins in balance.
  • L-Valine - has a stimulating effect. It maintains the metabolism of muscles, repairs tissues and balances nitrogen. Valine should be combined with Leucine and isoleucine.
  • Glutamine is especially recommended for people who suffer from problems such as irritable bowel syndrome, colitis, Crohn's Disease and anyone under heavy stress (including strenuous exercise) or recovering from injury or other trauma. It is felt that lack of L-glutamine leads to a loss of epithelial cell integrity in the lining of the intestines. This, in turn, may allow toxins and infectious agents to enter the body. Most research studies concerning glutamine and the gastrointestinal system involve the addition of L-glutamine.
  • L-glutamine the biologically active isomer of glutamine is widely used as a dietary supplement. It accounts for 30-35 percent of the amino acid nitrogen in the plasma. It contains two ammonia groups, one from its precursor, glutamate, and the other from free ammonia in the bloodstream.
  • glutamine can act as a buffer, accepting, and then releasing excess ammonia when needed to form other amino acids, amino sugars, nucleotides, and urea. This capacity to accept and donate nitrogen makes glutamine major vehicle for nitrogen transfer among tissues.
  • Hagen and her coauthors had previously shown that glutamine protects against cell death from H. pylori-produced ammonia. They observed that the damaging effects of ammonia on gastric cells could be reversed completely by the administration of L-glutamine.
  • the invention provides novel synergistic mesalamine co-crystals which comprise mesalmine and L-glutamine.
  • the said co-crystal improves the bioavailability of mesalamine and also increases the amount of mesalamine available at the colon, as L-glutamine has the tendency to accumulate in the colon. Further, the other side effects of mesalmine viz, flatulence will be mitigated as L-glutamine has the acid - base stabilization effect in the gastrointestinal fluids.
  • novel synergistic pharmaceutical co-crystals comprising Mesalamine and L- glutamine is useful in treating Crohn,s disease and Ulcerative colitis either alone or together with other modalities of treatment selected from corticosteroids, immunomodulators such as methotrexate, azathiopurine; monoclonal antibodies such as infliximab, certolizimab, natalizumab and other novel small molecule and biologic drugs.
  • novel synergistic pharmaceutical co-crystals comprising Mesalamine and L-glutamine is useful for the treatment caused due to infection by mycobacterial species especially Mycobacterium avium subspecies paratuberculosis (MAP).
  • mycobacterial species especially Mycobacterium avium subspecies paratuberculosis (MAP).
  • the synergistic pharmaceutical co-crystals comprising Mesalamine and L-glutamine is useful against inflammatory bowel disease caused due to infection by various mycobacterial species especially Mycobacterium avium subspecies paratuberculosis (MAP).
  • MAP Mycobacterium avium subspecies paratuberculosis
  • the synergistic pharmaceutical co-crystals comprising Mesalamine and L-glutamine is useful for the treatment caused due to infections by bacteria such as E.coli, Clostridium Difficile Co ⁇ Xs,Helicobacter pylori etc.
  • the synergistic pharmaceutical co-crystals comprising Mesalamine and L-glutamine is useful for the treatment of viral infections, microbial, fungal infections.
  • the present invention provides novel pharmaceutical composition
  • novel pharmaceutical composition comprising mesalamine and flavone co-crystals in association with one or more pharmaceutical carriers, wherein flavones are belonging to a class of 3-hydroxy flavone such as Quercetin.
  • Quercetin a plant derived flavonoid belongs to a class of 3-hydroxy flavone. It is used as a nutritional supplement and has demonstrated significant anti-inflammatory activity by inhibiting both manufacture and release of histamine and other allergic/inflammatory mediators. In addition, it acts as an anti-tumor agent; induces apoptosis and inhibits synthesis of heat shock proteins. It inhibits many enzyme systems including tyrosine protein kinase, phospholipase A2, phosphodiesterases, mitochondrial ATPase, PI 3-kinase and protein kinase C and can also activate Ca2+ and K+ channels [Merck Index]. It is also known as a potent inhibitor of CYP3A4and CYP2C9, which are enzymes that break down most drugs in the body.
  • Quercetin is insoluble in water and sparingly soluble in aqueous buffers. However it is soluble in organic solvents such ethanol, DMSO, DMF and the solubility in these solvents is 2mg/ml in ethanol and 30mg/ml in DMSO and DMF.
  • organic solvents such as ethanol, DMSO, DMF and the solubility in these solvents is 2mg/ml in ethanol and 30mg/ml in DMSO and DMF.
  • One characteristic feature of quercetin bioavailability is that the elimination of quercetin metabolites is quite slow, with reported half-lives ranging from 1 1 to 28 h. This could favor accumulation in plasma with repeated intakes.
  • the present invention relates to novel synergistic mesalamine co-crystals which comprise mesalamine and quercetin.
  • This co-crystal improves the bioavailability of mesalamine.
  • the anti-inflammatory effect of Mesalamine will be synergistically enhanced by Quercetin, thus effectively reducing the dosage levels.
  • the present invention provides novel pharmaceutical composition comprising mesalamine and nutraceuticals co-crystals in association with one or more pharmaceutical carriers.
  • Nutraceutical a term combining the words "nutrition” and “pharmaceutical,” is a food or food product that provides health and medical benefits, including the prevention and treatment of disease. Such products may range from isolated nutrients, dietary supplements and specific diets to genetically engineered foods, herbal products, processed foods such as cereals, soups, beverages and include but not limited to Alanine, Arginine, Ascorbic acid, Aspartic acid, Biotin, Calcium carbonate, Calcium citrate, Calcium glycerophosphate, Calcium oxide, Calcium pantothenate, Calcium phosphate, Calcium pyrophosphate, Calcium sulfate, Carotene, Choline bitartrate, Choline chloride, Copper gluconate, Cuprous iodide, Cysteine, Cystine, Ferric phosphate, Ferric pyrophosphate, Ferric sodium pyrophosphate, Ferrous gluconate, Ferrous lactate, Ferrous sulfate, Glycine, Histidine, Inositol, Iron reduced, Isole
  • the present invention discloses novel synergistic mesalamine and nutraceutical co-crystals which can be used as medically valuable compounds.
  • the present invention discloses preparation of mesalamine hydrochloride glutamine co-crystal in 1 : 1 ratio.
  • Mesalamine exists as zwitter ion which did not interact with glutamine under different conditions. Accordingly Mesalamine and conc.HCl taken in 1 :1 molar ratio are dissolved in methanol and then heated up to 55°C for half an hour. The resulting solution is filtered and kept for solvent evaporation to isolate mesalamine hydrochloride.
  • Mesalamine hydrochloride obtained from above is mixed with Glutamine and grounded in acetonitrile for 10 minutes using a mortar and pestle and left for solvent evaporation to obtain free flowing solid.
  • the resultant solid is subjected to analytical studies
  • the PXRD pattern shows that the co crystal is a different crystalline form as compared to the two formers (Table 2).
  • the NMR analysis indicates that the co-crystal was formed by 1 : 1 ratio of mesalamine hydrochloride and glutamine.
  • the co-crystal melts in-between the melting points of co-crystal formers (more often) or below their melting points (less often).
  • DSC analysis of the co-crystal in 1 :1 ratio of the present invention begins to decompose at 162.57°C which is lower than the melting point of mesalamine hydrochloride free(263°C) and glutamine (187.14°C).
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of mesalamine-L glutamine co-crystals of the current invention in association with one or more pharmaceutical carriers.
  • the co-crystals of the invention have the same pharmaceutical activity as its API.
  • the pharmaceutical composition of the invention may be any pharmaceutical form which maintains the crystalline form of a co-crystal of the invention.
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of mesalamine and quercertin co-crystals with one or more pharmaceutical carriers.
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of mesalamine and nutraceutical co- crystals with one or more pharmaceutical carriers.
  • the carriers/ excipients are added to the composition for variety of purposes.
  • Dosage forms include solid dosage forms such as tablets, powders, capsules, liquid dosage forms as well as parenteral dosage forms.
  • the dosage forms can also be prepared as sustained, controlled, modified and immediate dosage forms, preferably the dosage form is sustained release.
  • the active ingredient(s) and excipients can be formulated into compositions and dosage forms according to methods known in the art.
  • the pharmaceutical composition of the instant invention may be prepared in the form of raw powders or granules dispersed in a suitable aqueous or non-aqueous liquid(s), pellets, beads, micro or nano particles, micro or nano crystals or a solvated powders, sachets, semisolids, an Injectable preparations, a tablets, a capsules or a suitable specific two- or three-dimensional matrix compositions.
  • the composition may be prepared by the techniques of dry granulation, wet granulation and / or direct compression using aqueous / Non aqueous solvent further fabricate into the single layer, bilayer, and multilayer and / or multicoated capsule or tablet dosage forms, preferably, the pharmaceutical composition is a multi-layer.
  • composition of instant invention may be prepared in the form of suppositories such as enema, douche, pessary
  • the parental composition comprises intravenous, Intradermal (ID) Intramuscular (IM) Intraosseous (10) Intraperitoneal (IP) Intravenous (IV) Subcutaneous (SC) Intrathecal (IT) injections and the topical formulation comprises cream, gel, liniment or balm, lotion, or ointment, drops, transdermal patch etc.
  • composition of the instant invention may be extended to the development of micelle, emulsion and liposome formulations, including small molecules, peptides, proteins, nucleic acids, antisense and siRNA.
  • the novel co-crystal of Mesalamine hydrochloride and glutamine is useful for the treatment of Crohn's disease, ulcerative colitis, indeterminate colitis, inflammatory bowel disease caused due to mycobacterial species especially Mycobacterium avium subspecies paratuberculosis (MAP), viral infections, microbial, fungal infections, bacterial disease caused due to bacteria such as E.coli, Clostridium Difficile Colitis, Helicobacter pylori etc.
  • MAP Mycobacterium avium subspecies paratuberculosis
  • the novel co-crystal of Mesalamine hydrochloride and glutamine may be administered through abdomen intraperitonealy; abdominal stents that open into colon, laproscopic guided direct delivery to colon; also may be delivered in the form of rectal enema, rectal suppository and other forms of delivery through rectum.
  • the invention also provides methods for the treatment of the disorder discussed above.
  • Mesalmine co-crystals and pharmaceutical compositions containing them may, according to the invention, be administered using any amount, any form of pharmaceutical composition and any route of administration effective for the treatment.
  • the pharmaceutical compositions of this invention can be administered by any means that delivers the active pharmaceutical ingredient(s) to the site of the body whereby it can exert a therapeutic effect on the patient.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un nouveau co-cristal pharmaceutique synergique de mésalamine, ou ses sels pharmaceutiquement acceptables, utilisé comme principe actif conjointement avec des agents co-formateurs tels que les acides aminés alpha, des flavones ou des nutraceutiques pour traiter les affections abdominales inflammatoires, la maladie de Crohn, la colite ulcéreuse et la colite indéterminée.
PCT/IN2011/000902 2010-12-29 2011-12-29 Nouveaux co-cristaux/ sels moléculaires de mésalamine s'utilisant comme médicament anti-inflammatoire amélioré WO2012090224A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3160DE2010 2010-12-29
IN3160/DEL/2010 2010-12-29

Publications (1)

Publication Number Publication Date
WO2012090224A1 true WO2012090224A1 (fr) 2012-07-05

Family

ID=46382390

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2011/000902 WO2012090224A1 (fr) 2010-12-29 2011-12-29 Nouveaux co-cristaux/ sels moléculaires de mésalamine s'utilisant comme médicament anti-inflammatoire amélioré

Country Status (1)

Country Link
WO (1) WO2012090224A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2857008A1 (fr) * 2011-08-19 2015-04-08 Joy Development UG Agent thérapeutique combiné
CN105315272A (zh) * 2015-10-19 2016-02-10 天津大学 一种盐酸硫胺晶体产品的制备方法
CN107286035A (zh) * 2017-05-19 2017-10-24 华东师范大学 一种5‑氨基水杨酸药物共晶及其制备方法
US10426765B2 (en) 2012-06-15 2019-10-01 Conaris Research Institute Ag Pharmaceutical composition containing nicotinic acid and/or nicotinamide and/or tryptophan for positively influencing the intestinal microbiota
US10758552B2 (en) 2013-12-13 2020-09-01 Conaris Research Institute Ag Pharmaceutical composition containing combinations of nicotinamide and 5-aminosalicylic acid for beneficially influencing the intestinal microbiota and/or treating gastrointestinal inflammation
US10888555B2 (en) 2013-12-13 2021-01-12 Conaris Research Institute Ag Pharmaceutical composition containing nicotinic acid and/or nicotinamide for beneficially influencing blood lipid levels by modifying the intestinal microbiota
CN113233976A (zh) * 2021-05-08 2021-08-10 广州萃普生物科技有限公司 一种没食子酸和氨基乙酸共晶及含有该共晶的美白膏霜
JP2022518678A (ja) * 2019-02-04 2022-03-16 ディーエスエム アイピー アセッツ ビー．ブイ． 炎症性腸疾患の処置のための治療用配合物及び組成物
CN115245487A (zh) * 2021-04-27 2022-10-28 中国医学科学院药物研究所 美沙拉嗪与马来酸共晶物及制备方法和其组合物与用途
CN115259231A (zh) * 2022-07-13 2022-11-01 绵阳师范学院 一种去除硫酸锰中钙和镁杂质的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006119844A2 (fr) * 2005-05-11 2006-11-16 The Jordanian Pharmaceutical Manufacturing Co. Systeme d'administration medicamenteuse orale a liberation commandee
US20090036414A1 (en) * 2007-08-02 2009-02-05 Mutual Pharmaceutical Company, Inc. Mesalamine Formulations
US20100004198A1 (en) * 2007-11-30 2010-01-07 Allergan, Inc. Polysaccharide gel formulation having increased longevity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006119844A2 (fr) * 2005-05-11 2006-11-16 The Jordanian Pharmaceutical Manufacturing Co. Systeme d'administration medicamenteuse orale a liberation commandee
US20090036414A1 (en) * 2007-08-02 2009-02-05 Mutual Pharmaceutical Company, Inc. Mesalamine Formulations
US20100004198A1 (en) * 2007-11-30 2010-01-07 Allergan, Inc. Polysaccharide gel formulation having increased longevity

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2857008A1 (fr) * 2011-08-19 2015-04-08 Joy Development UG Agent thérapeutique combiné
US10426765B2 (en) 2012-06-15 2019-10-01 Conaris Research Institute Ag Pharmaceutical composition containing nicotinic acid and/or nicotinamide and/or tryptophan for positively influencing the intestinal microbiota
US10758552B2 (en) 2013-12-13 2020-09-01 Conaris Research Institute Ag Pharmaceutical composition containing combinations of nicotinamide and 5-aminosalicylic acid for beneficially influencing the intestinal microbiota and/or treating gastrointestinal inflammation
US10888555B2 (en) 2013-12-13 2021-01-12 Conaris Research Institute Ag Pharmaceutical composition containing nicotinic acid and/or nicotinamide for beneficially influencing blood lipid levels by modifying the intestinal microbiota
CN105315272A (zh) * 2015-10-19 2016-02-10 天津大学 一种盐酸硫胺晶体产品的制备方法
CN105315272B (zh) * 2015-10-19 2018-10-26 天津大学 一种盐酸硫胺晶体产品的制备方法
CN107286035A (zh) * 2017-05-19 2017-10-24 华东师范大学 一种5‑氨基水杨酸药物共晶及其制备方法
JP2022518678A (ja) * 2019-02-04 2022-03-16 ディーエスエム アイピー アセッツ ビー．ブイ． 炎症性腸疾患の処置のための治療用配合物及び組成物
CN115245487A (zh) * 2021-04-27 2022-10-28 中国医学科学院药物研究所 美沙拉嗪与马来酸共晶物及制备方法和其组合物与用途
CN113233976A (zh) * 2021-05-08 2021-08-10 广州萃普生物科技有限公司 一种没食子酸和氨基乙酸共晶及含有该共晶的美白膏霜
CN115259231A (zh) * 2022-07-13 2022-11-01 绵阳师范学院 一种去除硫酸锰中钙和镁杂质的方法
CN115259231B (zh) * 2022-07-13 2023-04-18 绵阳师范学院 一种去除硫酸锰中钙和镁杂质的方法

Similar Documents

Publication Publication Date Title
WO2012090224A1 (fr) Nouveaux co-cristaux/ sels moléculaires de mésalamine s'utilisant comme médicament anti-inflammatoire amélioré
TWI258371B (en) Chromium (III) alpha amino acid complexes
WO2006050585A2 (fr) Modulation de synthases d'oxyde nitrique par des betaines
JP2010502583A (ja) 非常に速い皮膚浸透率を有するアセトアミノフェン及び関連化合物の正荷電水溶性プロドラッグ
JP2009542797A (ja) アスピリンの正荷電水溶性プロドラッグ
ITMI951021A1 (it) Composizioni farmaceutiche e/o dietetiche ad attivita' antiossidante
CN101522692A (zh) 具有快速皮肤穿透速度的带正电荷的水溶性的昔康及其相关化合物的前药
EP2305237B1 (fr) Agent thérapeutique pour la stérilité masculine
EP2271350A1 (fr) Compositions et procédés pour une immunothérapie
JP2006507283A (ja) 抗酸化組成物
US20150246018A1 (en) N-acetyl l-cysteine chelates and methods for making and using the same
CN113527368B (zh) 化合物、抗癌药物的制备方法和用途
JPH10130153A (ja) 大腸癌、食道癌及び乳癌より選ばれた癌に用いる 抗悪性腫瘍剤
US9901602B2 (en) Ejaculum of animals as medicinal material and uses thereof in medicaments for treatment of diseases such as tumors, depression, etc
ES2913376B2 (es) Compuestos de curcumina y aminoacidos basicos
US20090016984A1 (en) Drug for Hyperphospheremia and Its Preparative Method
CN109674789B (zh) 羧胺三唑与谷氨酸摄取与代谢抑制剂在抗肿瘤中的用途
EP0650725A1 (fr) Compositions comprenant des sels de l'acide L-2-oxothiazolidine-4-carboxylique et leur utilisation pour stimuler la glutathione intracellulaire
CN101402583B (zh) 左旋肉碱磷酸二氢钙及其制备方法与用途
CN103656611A (zh) 一种水溶性维生素的组合药物
EP3649081A1 (fr) Complexes d'or (iii) solubles dans l'eau, procédés de production de complexes d'or (iii) solubles dans l'eau et leur utilisation
CN100360125C (zh) 一种含谷氨酰胺的复方组合物及其制药用途
JP5855599B2 (ja) 非常に速い皮膚浸透率を有するアセトアミノフェン及び関連化合物の正荷電水溶性プロドラッグ
WO2001037823A1 (fr) Produit derive de type nitrobenzene substitue trouvant une application comme medicament ou autres produits efficaces
CN103351308A (zh) 具有快速皮肤穿透速度的带正电荷的水溶性的对乙酰氨基酚及其相关化合物的前药

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11853265

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11853265

Country of ref document: EP

Kind code of ref document: A1