WO2006045870A1 - Composiciones farmacéuticas bucodispersables - Google Patents
Composiciones farmacéuticas bucodispersables Download PDFInfo
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- WO2006045870A1 WO2006045870A1 PCT/ES2005/000566 ES2005000566W WO2006045870A1 WO 2006045870 A1 WO2006045870 A1 WO 2006045870A1 ES 2005000566 W ES2005000566 W ES 2005000566W WO 2006045870 A1 WO2006045870 A1 WO 2006045870A1
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- Prior art keywords
- calcium
- composition according
- weight
- composition
- acid
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 7
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims abstract description 46
- 229930003316 Vitamin D Natural products 0.000 claims abstract description 29
- 235000019166 vitamin D Nutrition 0.000 claims abstract description 29
- 239000011710 vitamin D Substances 0.000 claims abstract description 29
- 150000003710 vitamin D derivatives Chemical class 0.000 claims abstract description 29
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229940046008 vitamin d Drugs 0.000 claims abstract description 28
- 239000011575 calcium Substances 0.000 claims abstract description 19
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 18
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 17
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 239000011737 fluorine Substances 0.000 claims abstract description 8
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 8
- 230000002265 prevention Effects 0.000 claims abstract description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000000203 mixture Substances 0.000 claims description 79
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 60
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 57
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 30
- 229960003563 calcium carbonate Drugs 0.000 claims description 30
- 239000003795 chemical substances by application Substances 0.000 claims description 26
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- 239000003765 sweetening agent Substances 0.000 claims description 20
- 159000000007 calcium salts Chemical class 0.000 claims description 18
- 229960005069 calcium Drugs 0.000 claims description 17
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
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- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 10
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- 150000007524 organic acids Chemical class 0.000 claims description 9
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- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
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- 239000002253 acid Substances 0.000 claims description 7
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
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- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 6
- 230000001939 inductive effect Effects 0.000 claims description 6
- 239000005913 Maltodextrin Substances 0.000 claims description 5
- 229940035034 maltodextrin Drugs 0.000 claims description 5
- XGRSAFKZAGGXJV-UHFFFAOYSA-N 3-azaniumyl-3-cyclohexylpropanoate Chemical compound OC(=O)CC(N)C1CCCCC1 XGRSAFKZAGGXJV-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- -1 alkali metal bicarbonates Chemical class 0.000 claims description 4
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 claims description 4
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- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 claims description 4
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- 229960002401 calcium lactate Drugs 0.000 claims description 4
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims description 4
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- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
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- 229960004711 sodium monofluorophosphate Drugs 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 235000013337 tricalcium citrate Nutrition 0.000 claims description 4
- 235000005979 Citrus limon Nutrition 0.000 claims description 3
- 244000131522 Citrus pyriformis Species 0.000 claims description 3
- 235000016623 Fragaria vesca Nutrition 0.000 claims description 3
- 235000011363 Fragaria x ananassa Nutrition 0.000 claims description 3
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 235000010323 ascorbic acid Nutrition 0.000 claims description 3
- 239000011668 ascorbic acid Substances 0.000 claims description 3
- 229960005070 ascorbic acid Drugs 0.000 claims description 3
- 239000001506 calcium phosphate Substances 0.000 claims description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 3
- 229960001714 calcium phosphate Drugs 0.000 claims description 3
- 235000011010 calcium phosphates Nutrition 0.000 claims description 3
- 229940093915 gynecological organic acid Drugs 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 235000005985 organic acids Nutrition 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 3
- 239000008109 sodium starch glycolate Substances 0.000 claims description 3
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- 238000006467 substitution reaction Methods 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 239000001736 Calcium glycerylphosphate Substances 0.000 claims description 2
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
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- 240000004760 Pimpinella anisum Species 0.000 claims description 2
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- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 229960002562 calcium glucoheptonate Drugs 0.000 claims description 2
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- UHHRFSOMMCWGSO-UHFFFAOYSA-L calcium glycerophosphate Chemical compound [Ca+2].OCC(CO)OP([O-])([O-])=O UHHRFSOMMCWGSO-UHFFFAOYSA-L 0.000 claims description 2
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- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical group [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/0007—Effervescent
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
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- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
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- A61K33/16—Fluorine compounds
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A61P3/02—Nutrients, e.g. vitamins, minerals
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
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- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- the present invention relates to oral pharmaceutical compositions, in the form of orodispersible tablets, containing calcium and, optionally, vitamin D and / or fluorine together with pharmaceutically acceptable excipients, useful for the treatment or prevention of osteoporosis or other diseases characterized by bone loss
- the skeleton performs functions in the support and protection of soft organs as well as in mineral and acid-base homeostasis.
- the bone has a complex anatomical-functional organization.
- a solid organic matrix (osteoid) formed by type I collagen is distinguished, strengthened with the deposit of calcium, magnesium, phosphate, carbonate, citrate, chlorine and fluorine mineral salts.
- the most abundant salt is hydroxyapatite (Ca 10 (PO 4 ) and (OH) 2 ) that forms crystals entwined with collagen fibers.
- Bone lamellae have cavities that house cells (osteoclasts, osteoblasts and osteocytes) and are connected to each other by the Havers canals, through which interstitial fluids and blood circulate.
- osteoclasts osteoclasts, osteoblasts and osteocytes
- the cortical, compact and with thick layers of calcified osteoid the cortical, compact and with thick layers of calcified osteoid
- the trabecular, less dense and with numerous bone spicules Bone formation begins in the womb and continues during childhood and adolescence until skeletal maturity. During the remaining life, the bone is not a static element but is a very active tissue that It is constantly renewing through a remodeling mechanism. This mechanism consists in the destruction of small amounts of bone made by osteoclasts.
- osteoblasts bone formation
- systemic factors parathyroid hormone, calcitonin, vitamin D
- local factors cytokines, growth factors and peptides
- Osteoporosis is the most common alteration of the skeleton, in which there is a decrease in bone mass per unit volume compared to what is considered normal for a certain age, sex and race, but the relationship between the organic and organic phases is maintained. Mineral This relationship can be altered in other metabolic bone diseases such as osteomalacia.
- Osteoporosis can be of different types: primary, secondary, idiopathic and localized.
- Primary osteoporosis is caused by menopause (Type I, characterized by loss of trabecular bone) and aging (Type II, characterized by loss of cortical bone).
- Secondary osteoporosis can be caused by various diseases, certain medications or prolonged immobilization. Idiopathic osteoporosis has an unknown cause.
- osteoporosis type I osteoclastic activity predominates and bone loss is greater than in normal conditions, osteoblastic activity is normal but is not able to compensate for bone loss.
- osteoporosis type II osteoclastic activity is normal but osteoblast is diminished and is not able to compensate for the loss.
- Calcium is the predominant mineral in bone and is normally contributed to the body through diet. However, in certain cases this contribution is not sufficient and supplements of this mineral should be prescribed in order to prevent or treat osteoporosis and other diseases characterized by bone loss.
- the recommended amount of calcium varies depending on the authors, the age of the person and the salt administered. In general, the recommended intake for an adult is usually between 800 and 1500 mg / day.
- vitamin D refers to a group of molecules with a steroid structure that include cholecalciferol (vitamin D3), ergocalciferol (vitamin D2), its biologically active metabolites (particularly 1,25-dihydroxycholecalciferol) and its precursors (provitamin D2 present in food from plant origin, provitamin D3 available in food of animal origin).
- This vitamin promotes intestinal absorption of calcium, phosphate and magnesium ions, contributes to the regulation of calcium in plasma by acting in the process of bone formation and resorption and stimulates the reabsorption of calcium in the kidney.
- the crucial effect of vitamin D on bone is to provide an appropriate balance of calcium and phosphorus to contribute to mineralization.
- Vitamin D is produced in the body by the action of the sun's rays on the precursors obtained from food. However, in situations of deficiency diets and / or poor exposure to sunlight, it will be necessary to administer supplements with vitamin D to prevent or treat osteoporosis and other bone diseases.
- vitamin D is fat soluble and accumulate in the body. It should not be administered in supraphysiological concentrations because they alter renal, neurological and digestive function.
- the recommended amounts of vitamin D range between 200 and 800 IU / day, depending on the person's age and nutritional status.
- Fluorine is mainly associated with calcified tissues (bones and teeth). It is a known inducer of osteoblastic proliferation. Normally it is supplied to the body by drinking water and food but in certain cases it may be necessary to prescribe supplements, being sodium fluoride (FNa) and sodium monofluorophosphate
- the optimal therapeutic range of fluorine ions is 10 to 50 mg / day for an adult human. It is recommended not to administer more than 30 mg of fluoride / day as it has been observed that when doses of 60 mg of FNa / day are used, the formation of an abnormal bone occurs.
- compositions containing calcium and, optionally, vitamin D and / or fluorine, in the prevention and treatment of osteoporosis is widely known.
- pharmaceutical compositions which contain calcium in the form of salt, preferably calcium phosphate, vitamin D and a binding agent chosen from propylene glycol, polyethylene glycol of PM between 300 and 1500, liquid paraffin or silicone oil .
- WO 96/09036 describes therapeutic combinations of vitamin D and a calcium salt, preferably calcium carbonate, which further comprise a first binder in synergistic combination with a diluent, a second binder and a lubricant, the diluent and the second being binder a sweetener.
- the first binder is selected from a cellulose, maltodextrin and polyvinylpyrrolidone, the diluent is preferably xylitol, the second binder is preferably sorbitol and the lubricant is generally magnesium stearate.
- WO 92/19251 describes nutritional supplements that contain calcium, specifically in the form of a calcium malate citrate salt, vitamin D and optionally an estrogen.
- US 3345265 describes oral multilayer tablets with a central core of calcium salt and an outer fluoride shell, useful as a nutritional supplement during pregnancy.
- the commercially available pharmaceutical calcium formulations present a number of problems that make them not acceptable to everyone.
- Tablets and capsules are the preferred pharmaceutical forms for drug administration because they can be exactly dosed, easily manufactured on a large scale and contribute to good treatment compliance. However, certain patients have difficulty swallowing hard gelatin tablets and capsules and, consequently, do not take the medication as prescribed.
- Orodispersible tablets can be defined as solid forms that disintegrate or dissolve instantaneously or rapidly in the oral cavity without the need to administer liquids forming a solution or suspension that can be swallowed easily. They are also referred to as fast-melt, fast-dissolving, orodispersible, orodisintegrable, orodisintegrable or bucoluble tablets.
- the orodispersible tablets can be prepared by different procedures, mainly freeze-drying (lyophilization), forming by molding and direct compression.
- the first two procedures allow to obtain orodispersible tablets that disintegrate in approximately 30 seconds but have low physical resistance and high friability.
- direct compression provides tablets with less friability but that disintegrate in longer time.
- the disintegration efficiency is strongly affected by the size and hardness of the orodispersible tablet.
- Optimum disintegration properties are often associated with a medium or small size and / or low physical resistance (high friability and low hardness). Consequently, a difficulty typical of formulations in the form of orodispersible tablets is to obtain adequate friability and hardness values at the same time as acceptable disintegration times.
- the disintegration time of an orodispersible tablet must be less than 3 minutes.
- the inventors of the present invention have found that surprisingly, despite the limitation. representing the amount of excipients that can be added to the composition, the use of certain excipients allows, by a direct compression method, orodispersible tablets of a calcium salt and, optionally, vitamin D and / or a fluorine salt, compliant disintegration time required by the pharmacopoeia while possessing size, integrity and adequate mechanical strength, allowing 'to be transported without fragility conditions. They also manage to obtain orodispersible tablets with adequate friability and hardness.
- the excipients used in the present invention allow rapid tablets to be prepared. disintegration in the mouth and at the same time of pleasant taste and texture, which provides comfort and pleasure to the patient and, consequently, improves treatment compliance.
- the orodispersible tablets of the present invention when obtained by direct compression, have a lower manufacturing cost than, for example, lyophilized tablets, since they use conventional production and packaging equipment, commonly available excipients and a limited number of steps.
- a first aspect of the present invention relates to oral pharmaceutical compositions, in the form of orodispersible tablets, containing as active ingredient (s) elemental calcium and, optionally, vitamin D and / or fluorine, together with excipients pharmaceutically acceptable.
- a second aspect of the present invention relates to use of orodispersible calcium tablets and, optionally, vitamin D and / or fluoride, in the prevention or treatment of osteoporosis or other diseases characterized by bone loss.
- a third aspect of the present invention relates to the process for preparing orodispersible calcium tablets and, optionally, vitamin D and / or fluoride, by direct compression.
- formulations of this invention comprise elemental calcium in an amount between 15 and 35% by weight of the formulation, at least one disintegrating agent and at least one sweetening agent.
- the orodispersible tablets of the present invention comprise: - between 400 and 700 mg of elemental calcium; at least one disintegrating agent; at least one sweetening agent.
- the orodispersible tablets of the present invention comprise: - between 400 and 700 mg of elemental calcium;
- vitamin D between 100 and 500 U.I. of vitamin D; at least one disintegrating agent; at least one sweetening agent.
- the orodispersible tablets of the present invention comprise: between 400 and 700 mg of elemental calcium;
- vitamin D between 100 and 500 U.I. of vitamin D; between 2 and 30 mg of fluoride; at least one disintegrating agent; - at least one sweetening agent.
- Elemental calcium is provided in the form of a Salt .
- the calcium salt is selected from calcium carbonate, calcium pidolate, calcium lactate, calcium citrate, calcium gluconate, calcium chloride, calcium glucoheptonate, calcium glycerophosphate, calcium phosphate and mixtures thereof.
- the calcium salt is selected from the group consisting of calcium carbonate, calcium gluconate, calcium lactate, calcium citrate and mixtures thereof.
- the calcium salt is calcium carbonate in a percentage between 45 and 90% by weight of the formulation, more preferably between 70 and 80%.
- This salt exerts a double function as a source of calcium and as an agent capable of releasing carbon dioxide
- the calcium salt can be pregranulated with maltodextrins or with pregelatinized starch, in order to obtain a raw material with adequate flow and compressibility characteristics.
- mixtures of calcium carbonate / maltodextrin with a weight ratio of 95/5 and 90/10 are used.
- vitamin D can be stabilized with antioxidant agents.
- vitamin D stabilized with DL- ⁇ -tocopherol is used.
- Fluorine is provided in the form of a salt.
- the fluorine salt is selected from monofluorophosphate and sodium fluoride.
- the fluorine salt is sodium monofluorophosphate in an amount between 15 and 230 mg, more preferably between 50 and 200 mg.
- the disintegrating agent is preferably selected from crospovidone, croscarmellose sodium, guar gum, sodium starch glycolate and cellulose derivatives such as low-grade hydroxypropylcellulose.
- the disintegrating agent is chosen from crospovidone, croscarmellose sodium, sodium starch glycolate and low-grade hydroxypropylcellulose, and is incorporated in an amount between 1% and 10% by weight of the formulation.
- the disintegrating agent is low-grade hydroxypropylcellulose (L-HPC), added in an amount between 4% and 6% by weight of the formulation.
- L-HPC low-grade hydroxypropylcellulose
- the L-HPC is chosen from two 'varieties (LH-LH-Il and 21) of different particle size, density and degree of substitution.
- the sweetening agent is preferably an intense flavor sweetener chosen from the group consisting of aspartame, sodium saccharin, sodium cyclamate, potassium acesulfame and mixtures thereof, and is added in an amount between 0.1% and 1% by weight of the formulation.
- the intense flavor sweetener is selected from aspartame and mixtures containing it. • In an even more preferred embodiment, the intense flavor sweetener is aspartame, added in an amount between 0.15% and 0.55% by weight of the formulation.
- the intense flavor sweetener may optionally be accompanied by at least one aroma selected from the group consisting of essences of orange, lemon, strawberry, berries, mint and anise, in an amount between 0.01% and 1% by weight of the formulation.
- the orodispersible tablets of the present invention may also contain other pharmaceutically acceptable excipients.
- an effervescent agent comprising an agent capable of releasing CO 2 together with an inducing agent of release of CO2.
- the agent capable of releasing CO 2 can be selected from carbonates and alkali metal bicarbonates.
- the agent capable of releasing CO 2 is calcium carbonate.
- the CO 2 releasing agent can be chosen from organic acids, their acid salts and mixtures thereof.
- the CO 2 release inducing agent is an organic acid selected from tartaric acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, citric acid, acid salts of said acids and mixtures thereof.
- the organic acid is chosen from anhydrous, tartaric, ascorbic citric acid and mixtures thereof. And more preferably it is anhydrous citric acid in an amount between 2% and 25% by weight of the formulation.
- the CO 2 release inducing agent is preferably in solid form and can be used in different particle sizes, chosen between powder and granular form.
- the effervescent agent is constituted by calcium carbonate / citric acid in a weight ratio between 10/1 and 2/1, more preferably between 8/1 and 4/1.
- the tablets of the present invention will also contain at least one diluent-binder selected from the group consisting of lactose, plasdone, maltodextrin, microcrystalline cellulose, and dextrates in an amount between 1% and 10% by weight of the formulation.
- the diluent is lactose, incorporated in an amount between 1% and 5% by weight of the formulation.
- the formulations will also contain at least one lubricating agent chosen from the group consisting of stearic acid, magnesium stearate, sodium stearyl fumarate, calcium stearate, and polyethylene glycols in an amount between 0.5% and 5% by weight of the formulation.
- the lubricant is stearic acid, added in an amount between 1% and 3% by weight of the formulation.
- the tablets of the present invention may also contain at least one low intensity flavor sweetener selected from the group consisting of sorbitol, mannitol, xylitol, fructose, maltose, maltitol, lactitol and mixtures thereof, in an amount between 1% and 20% in formulation weight
- at least one low intensity flavor sweetener selected from the group consisting of sorbitol, mannitol, xylitol, fructose, maltose, maltitol, lactitol and mixtures thereof, in an amount between 1% and 20% in formulation weight
- the tablets will not contain a mild flavor sweetener.
- the orodispersible tablets of the present invention comprise: - between 1250 mg and 1750 mg of calcium carbonate; between 50 mg and 150 mg of low-grade hydroxypropylcellulose; between 100 mg and 450 mg of citric acid; between 4 mg and 15 mg of aspartame; - optionally, between 300 U.I. and 500 U.I. of vitamin D; optionally, between 50 mg and 200 mg of monofluorophosphate.
- Both the excipients and the active ingredients used in the tablets of the present invention are known and can be obtained from commercial sources.
- the orodispersible tablets of the present invention are useful in the treatment or prevention of osteoporosis or other diseases characterized by bone loss.
- the tablets of the present invention are prepared following a direct compression technique.
- sweetener, disintegrant and, optionally, vitamin D are mixed.
- the premix is placed in a mixer together with the calcium salt and, optionally, organic acid, aroma, diluent-binder and / or lubricant.
- the obtained mixture is compressed in a rotary compressing machine.
- the calcium salt, disintegrant and, optionally, organic acid and / or diluent-binder are premixed.
- the mixer premix is removed and a quarter by weight of the same is returned to the same mixer. It is incorporated in the form of a sandwich (inside) sweetener and, optionally, vitamin D and / or aroma and mixed.
- the orodispersible tablets obtained have • adequate technical characteristics and obtained good acceptance in trials with healthy volunteers.
- 95% MD and 90% MD calcium carbonate means granulated calcium carbonate with 5% and 10% by weight of maltodextrin, respectively;
- Cholecalciferol represents vitamin D3. stabilized with DL- ⁇ - ⁇ tocopherol in which 1 mg of cholecalciferol is equivalent to 100 IU of active substance.
- Assays to determine breaking strength, friability and disintegration time of tablets were performed according to the Royal Spanish Pharmacopoeia, 2 Ed., 2002.
- Disintegration time (min) 1.0-1.8
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Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
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PL05807929T PL1837019T3 (pl) | 2004-10-25 | 2005-10-24 | Kompozycja farmaceutyczna rozpadająca się w ustach |
JP2007538445A JP5090918B2 (ja) | 2004-10-25 | 2005-10-24 | 経口用分散性医薬組成物 |
DK05807929.4T DK1837019T3 (da) | 2004-10-25 | 2005-10-24 | Orale dispergerbare farmaceutiske sammensætninger |
ES05807929T ES2394456T3 (es) | 2004-10-25 | 2005-10-24 | Composiciones farmacéuticas bucodispersables |
US11/577,861 US20090041860A1 (en) | 2004-10-25 | 2005-10-24 | Orally-dispersible pharmaceutical compositions |
EP05807929A EP1837019B1 (en) | 2004-10-25 | 2005-10-24 | Orally-dispersible pharmaceutical compositions |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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ESP200402560 | 2004-10-25 | ||
ES200402560A ES2255429B1 (es) | 2004-10-25 | 2004-10-25 | Composiciones farmaceuticas bucodispersables. |
Publications (1)
Publication Number | Publication Date |
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WO2006045870A1 true WO2006045870A1 (es) | 2006-05-04 |
Family
ID=36227498
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/ES2005/000566 WO2006045870A1 (es) | 2004-10-25 | 2005-10-24 | Composiciones farmacéuticas bucodispersables |
Country Status (10)
Country | Link |
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US (1) | US20090041860A1 (es) |
EP (1) | EP1837019B1 (es) |
JP (1) | JP5090918B2 (es) |
KR (1) | KR20070072610A (es) |
DK (1) | DK1837019T3 (es) |
ES (2) | ES2255429B1 (es) |
PL (1) | PL1837019T3 (es) |
PT (1) | PT1837019E (es) |
RU (1) | RU2405541C2 (es) |
WO (1) | WO2006045870A1 (es) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
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UA95093C2 (uk) | 2005-12-07 | 2011-07-11 | Нікомед Фарма Ас | Спосіб одержання кальцієвмісної сполуки |
BRPI0817927A2 (pt) * | 2007-10-01 | 2015-04-07 | Lesvi Laboratorios Sl | Comprimidos orodispersiveis |
WO2009151090A1 (ja) * | 2008-06-12 | 2009-12-17 | 株式会社 三和化学研究所 | 炭酸カルシウム含有速崩壊性製剤 |
TR200900878A2 (tr) * | 2009-02-05 | 2010-08-23 | Bi̇lgi̇ç Mahmut | Tek bir dozaj formunda kombine edilen farmasötik formülasyonlar |
JP4562797B1 (ja) * | 2009-05-29 | 2010-10-13 | マイラン製薬株式会社 | 沈降炭酸カルシウムを有効成分とする口腔内崩壊錠 |
TR200908237A2 (tr) * | 2009-11-02 | 2011-05-23 | Bi̇lgi̇ç Mahmut | Kalsiyum ve D vitamini içeren farmasötik bileşimler. |
DE102010043318A1 (de) * | 2010-11-03 | 2012-05-03 | Klaus F. Kopp | Calciumcarbonat enthaltende Zusammensetzung |
CN102160648B (zh) * | 2011-03-11 | 2012-06-27 | 陕西科技大学 | 一种口腔速崩钙片及其制备方法 |
EP2919744B1 (en) | 2012-11-16 | 2020-09-02 | EUSA Pharma (UK) Ltd | Effervescent tablet |
JP6554034B2 (ja) * | 2013-08-09 | 2019-07-31 | 日東薬品工業株式会社 | カルシウム剤 |
KR20180062063A (ko) * | 2016-11-30 | 2018-06-08 | (주) 메티메디제약 | 서방형 항암용 약학 조성물 |
WO2019004984A2 (en) * | 2017-05-29 | 2019-01-03 | Biofarma Ilac Sanayi Ve Ticaret A.S. | PHARMACEUTICAL FORMULATION COMPRISING CHOLECALCIFEROL |
IT201700099708A1 (it) * | 2017-09-06 | 2019-03-06 | Abiogen Pharma Spa | Composizione per l’integrazione di calcio |
PT3799864T (pt) | 2019-10-02 | 2023-05-25 | Intas Pharmaceuticals Ltd | Composições farmacêuticas sólidas efervescentes essencialmente isentas de sódio |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5965162A (en) * | 1993-09-10 | 1999-10-12 | Fuisz Technologies Ltd. | Process for forming chewable quickly dispersing multi-vitamin preparation and product therefrom |
US6475510B1 (en) * | 1997-12-19 | 2002-11-05 | Smithkline Beecham Corporation | Process for manufacturing bite-dispersion tablets |
ES2192136A1 (es) * | 2002-01-04 | 2003-09-16 | Italfarmaco Sa | Composiciones farmaceuticas para el tratamiento o prevencion de la osteoporosis. |
Family Cites Families (1)
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US6716454B2 (en) * | 1994-09-23 | 2004-04-06 | Laboratorie Innothera, Société Anonyme | Therapeutic combination of vitamin and calcium in unitary galenic tablet form, a method of obtaining it, and the use thereof |
-
2004
- 2004-10-25 ES ES200402560A patent/ES2255429B1/es active Active
-
2005
- 2005-10-24 RU RU2007116432/15A patent/RU2405541C2/ru active
- 2005-10-24 US US11/577,861 patent/US20090041860A1/en not_active Abandoned
- 2005-10-24 JP JP2007538445A patent/JP5090918B2/ja active Active
- 2005-10-24 WO PCT/ES2005/000566 patent/WO2006045870A1/es active Application Filing
- 2005-10-24 PL PL05807929T patent/PL1837019T3/pl unknown
- 2005-10-24 PT PT05807929T patent/PT1837019E/pt unknown
- 2005-10-24 KR KR1020077011688A patent/KR20070072610A/ko active Search and Examination
- 2005-10-24 DK DK05807929.4T patent/DK1837019T3/da active
- 2005-10-24 EP EP05807929A patent/EP1837019B1/en active Active
- 2005-10-24 ES ES05807929T patent/ES2394456T3/es active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5965162A (en) * | 1993-09-10 | 1999-10-12 | Fuisz Technologies Ltd. | Process for forming chewable quickly dispersing multi-vitamin preparation and product therefrom |
US6475510B1 (en) * | 1997-12-19 | 2002-11-05 | Smithkline Beecham Corporation | Process for manufacturing bite-dispersion tablets |
ES2192136A1 (es) * | 2002-01-04 | 2003-09-16 | Italfarmaco Sa | Composiciones farmaceuticas para el tratamiento o prevencion de la osteoporosis. |
Also Published As
Publication number | Publication date |
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EP1837019A1 (en) | 2007-09-26 |
PT1837019E (pt) | 2012-11-23 |
JP5090918B2 (ja) | 2012-12-05 |
ES2394456T3 (es) | 2013-01-31 |
ES2255429B1 (es) | 2007-08-16 |
RU2007116432A (ru) | 2008-11-27 |
PL1837019T3 (pl) | 2013-02-28 |
EP1837019B1 (en) | 2012-08-29 |
RU2405541C2 (ru) | 2010-12-10 |
JP2008517981A (ja) | 2008-05-29 |
KR20070072610A (ko) | 2007-07-04 |
ES2255429A1 (es) | 2006-06-16 |
US20090041860A1 (en) | 2009-02-12 |
DK1837019T3 (da) | 2012-11-12 |
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