MXPA96005660A - Oral liquid formulations of alendron - Google Patents
Oral liquid formulations of alendronInfo
- Publication number
- MXPA96005660A MXPA96005660A MXPA/A/1996/005660A MX9605660A MXPA96005660A MX PA96005660 A MXPA96005660 A MX PA96005660A MX 9605660 A MX9605660 A MX 9605660A MX PA96005660 A MXPA96005660 A MX PA96005660A
- Authority
- MX
- Mexico
- Prior art keywords
- pharmaceutical composition
- alendronate
- liquid
- powder
- aqueous solution
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 30
- 239000007788 liquid Substances 0.000 title claims description 17
- 229940062527 Alendronate Drugs 0.000 claims abstract description 47
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims abstract description 46
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
- 239000007864 aqueous solution Substances 0.000 claims abstract description 13
- 239000008139 complexing agent Substances 0.000 claims abstract description 10
- 238000001556 precipitation Methods 0.000 claims abstract description 4
- 239000003937 drug carrier Substances 0.000 claims abstract 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 42
- 210000000988 Bone and Bones Anatomy 0.000 claims description 19
- 239000000843 powder Substances 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical group [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims description 14
- 239000001509 sodium citrate Substances 0.000 claims description 14
- 239000011778 trisodium citrate Substances 0.000 claims description 14
- 238000009472 formulation Methods 0.000 claims description 13
- 239000008213 purified water Substances 0.000 claims description 11
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 9
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 239000005720 sucrose Substances 0.000 claims description 9
- 239000006188 syrup Substances 0.000 claims description 9
- 235000020357 syrup Nutrition 0.000 claims description 9
- 208000001132 Osteoporosis Diseases 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- 230000000152 swallowing Effects 0.000 claims description 7
- 240000002799 Prunus avium Species 0.000 claims description 6
- 235000010401 Prunus avium Nutrition 0.000 claims description 6
- 235000014441 Prunus serotina Nutrition 0.000 claims description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
- 229940075582 Sorbic Acid Drugs 0.000 claims description 5
- 235000010199 sorbic acid Nutrition 0.000 claims description 5
- 239000004334 sorbic acid Substances 0.000 claims description 5
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 claims description 5
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 4
- 208000003393 Mammary Paget's Disease Diseases 0.000 claims description 4
- 208000010191 Osteitis Deformans Diseases 0.000 claims description 4
- 229940000425 combination drugs Drugs 0.000 claims description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- 235000011187 glycerol Nutrition 0.000 claims description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- CVHZOJJKTDOEJC-UHFFFAOYSA-N Saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 3
- 229940081974 Saccharin Drugs 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 235000016337 monopotassium tartrate Nutrition 0.000 claims description 3
- 239000000546 pharmaceutic aid Substances 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 235000019204 saccharin Nutrition 0.000 claims description 3
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 claims description 3
- 241000282414 Homo sapiens Species 0.000 claims description 2
- KYKNRZGSIGMXFH-ZVGUSBNCSA-M Potassium bitartrate Chemical compound [K+].OC(=O)[C@H](O)[C@@H](O)C([O-])=O KYKNRZGSIGMXFH-ZVGUSBNCSA-M 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 claims 1
- 206010072736 Rheumatic disease Diseases 0.000 claims 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims 1
- 239000002552 dosage form Substances 0.000 claims 1
- 229940095064 tartrate Drugs 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 description 20
- 239000000796 flavoring agent Substances 0.000 description 10
- 239000003086 colorant Substances 0.000 description 8
- 230000001105 regulatory Effects 0.000 description 8
- 208000006386 Bone Resorption Diseases 0.000 description 6
- 230000024279 bone resorption Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 235000019634 flavors Nutrition 0.000 description 5
- 235000013355 food flavoring agent Nutrition 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 230000032683 aging Effects 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drugs Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 239000006186 oral dosage form Substances 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- 230000002188 osteogenic Effects 0.000 description 3
- 230000001575 pathological Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- IAOZJIPTCAWIRG-QWRGUYRKSA-N Aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 2
- 229960003438 Aspartame Drugs 0.000 description 2
- 108010011485 Aspartame Proteins 0.000 description 2
- 208000003432 Bone Disease Diseases 0.000 description 2
- 208000010392 Bone Fractures Diseases 0.000 description 2
- BJHIKXHVCXFQLS-UYFOZJQFSA-N Fructose Natural products OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- 210000002997 Osteoclasts Anatomy 0.000 description 2
- 208000005368 Osteomalacia Diseases 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 239000000605 aspartame Substances 0.000 description 2
- 235000010357 aspartame Nutrition 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 150000004696 coordination complex Chemical class 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N 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 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000002969 morbid Effects 0.000 description 2
- 201000009251 multiple myeloma Diseases 0.000 description 2
- 230000002148 osteoclast Effects 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000008399 tap water Substances 0.000 description 2
- 235000020679 tap water Nutrition 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- SKOABMZZDZOFGK-UHFFFAOYSA-L C(=O)([O-])C(O)C(O)C(=O)[O-].[Na+].[K+].C(CC(O)(C(=O)O)CC(=O)O)(=O)O Chemical compound C(=O)([O-])C(O)C(O)C(=O)[O-].[Na+].[K+].C(CC(O)(C(=O)O)CC(=O)O)(=O)O SKOABMZZDZOFGK-UHFFFAOYSA-L 0.000 description 1
- 229940069078 Citric Acid / sodium citrate Drugs 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 229940031574 HYDROXYMETHYL CELLULOSE Drugs 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010020707 Hyperparathyroidism primary Diseases 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N Methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- NKAAEMMYHLFEFN-UHFFFAOYSA-M Monosodium tartrate Chemical compound [Na+].OC(=O)C(O)C(O)C([O-])=O NKAAEMMYHLFEFN-UHFFFAOYSA-M 0.000 description 1
- 229940100688 Oral Solution Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M Sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- HELHAJAZNSDZJO-UHFFFAOYSA-L Sodium tartrate Chemical compound [Na+].[Na+].[O-]C(=O)C(O)C(O)C([O-])=O HELHAJAZNSDZJO-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FDZXATKOVUCHQP-UHFFFAOYSA-M [Na+].OP(O)(=O)OP(O)(=O)OP(O)([O-])=O Chemical compound [Na+].OP(O)(=O)OP(O)(=O)OP(O)([O-])=O FDZXATKOVUCHQP-UHFFFAOYSA-M 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 201000001320 atherosclerosis Diseases 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- GOMCKELMLXHYHH-UHFFFAOYSA-L dipotassium;phthalate Chemical compound [K+].[K+].[O-]C(=O)C1=CC=CC=C1C([O-])=O GOMCKELMLXHYHH-UHFFFAOYSA-L 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- HQWKKEIVHQXCPI-UHFFFAOYSA-L disodium;phthalate Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C([O-])=O HQWKKEIVHQXCPI-UHFFFAOYSA-L 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 230000030991 negative regulation of bone resorption Effects 0.000 description 1
- 230000000474 nursing Effects 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- ASHGTUMKRVIOLH-UHFFFAOYSA-L potassium;sodium;hydrogen phosphate Chemical compound [Na+].[K+].OP([O-])([O-])=O ASHGTUMKRVIOLH-UHFFFAOYSA-L 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 201000000981 primary hyperparathyroidism Diseases 0.000 description 1
- MILWSGRFEGYSGM-UHFFFAOYSA-N propane-1,2-diol;propane-1,2,3-triol Chemical compound CC(O)CO.OCC(O)CO MILWSGRFEGYSGM-UHFFFAOYSA-N 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019980 sodium acid phosphate Nutrition 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- -1 that is to say Chemical compound 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
Abstract
The present invention relates to a pharmaceutical composition characterized in that it comprises a pharmaceutically effective amount of alendronate, in a pharmaceutically acceptable carrier and a sufficient amount of a buffer to maintain the pH of the composition on a scale of 2 to 8 and a complexing agent to prevent the precipitation of alendronate in the aqueous solution
Description
ORAL LIQUID FORMULATIONS flLENDRONATO PE
FIELD OF THE INVENTION The present invention is generally related to the use of oral liquid formulations of alendronate, that is to say, monosodium triphosphate of 4-amino-l-hydroxybutylidene-1,1-bisphosphonic acid, to inhibit bone resorption in the nascent humans who have difficulty swallowing. BACKGROUND OF THE INVENTION Normal bones are living tissues that undergo constant resorption and redeposition of calcium, with the essential effect of maintaining constant mineral balance. The dual process is commonly called "bone cycle". In normal bones that are growing, the mineral deposition is in equilibrium with the mineral resorption, while
.that in certain pathological conditions, bone resorption exceeds bone deposition, for example due to malignancy or primary hyperparathyroidism, or in osteoporosis. In other pathological conditions the calcium deposition can take place in inconvenient amounts and areas leading for example to heterotopic calcification, osteoarthritis, nephritic and vesicular calculi, atherosclerosis, and Paget's disease which is a combination of na Abnormally high bone resorption followed by abnormal calcium deposition.
Alendronate, rnonosodium tri-diet of 4-amino-l-hydroxybutylidene-1, 1-bisphosphonic acid, is an agent to combat bone resorption in bone diseases including osteoporosis and is described as composition, method of use and synthesis together with other pharmaceutically acceptable salts in U.S. Patents 4,922,007 and 5,019,651 (both transferred to Merck). There are situations in which, for example, an aging child is undergoing alendronate therapy for osteoporosis (ie bone thinning) or is considered to be a risk for developing osteoporosis and at the same time experiencing difficulty. to swallow. However, alendronate is usually administered orally to all patients in the form of a tablet. The availability of only one solid oral dosage form is
- A disadvantage for some patients who can not easily swallow tablets. In addition, these patients can coonsit a significant percentage of the population of patients treated with alendronate, since the drug is also designed for the population of female patients who are aging. What is desired in these cases is an effective therapy to optimally treat this population of female patients who are aging with an improved oral formulation that overcomes the problem of difficulty swallowing. BRIEF DESCRIPTION OF THE INVENTION The present invention provides a method for treating and / or preventing bone deterioration in an individual having difficulty swallowing by not administering to said patient a pharmaceutically effective amount of alendronate, in an oral liquid formulation. The liquid formulation may exist in the form of syrup, aqueous solution or reconstituted powder of
- alendronate in water solution and contain regulator to control the pH of the solution and a complexing agent to prevent the formation of insolubles alendronate complexes. The oral liquid pharmaceutical composition of this invention contains a pharmaceutically effective amount of alendronate in a pharmaceutically acceptable liquid carrier, for example purified water, and a regulator, for example.
Citrate, to maintain the pH at 2-8 and preferably 4-6 and a complexing agent, for example citrate or EDTA, to inhibit the precipitation of alendronate in an aqueous medium. The above aqueous solution containing a high concentration of sugar is also provided, providing a syrup to which flavor may be added for convenience of marketing. Also provided is a pharmaceutical composition which constitutes a powder for reconstitution containing a pharmaceutically effective amount of alendronate in a dry pharmaceutically acceptable excipient also in the presence of a regulator, eg citrate, and a complexing agent, said formulating agent being soluble. powder in water.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED MODALITIES
The oral solutions of alendronate, in the form of syrup, aqueous solution or reconstituted aqueous solution of powder, offer the advantages of ease of administration,
- increasing compliance with patients who have difficulty swallowing solid oral dosage forms, a powder for reconstitution also offers the additional advantage of minimizing storage space in nursing homes, pharmacies, hospitals and warehouses. These formulations have the advantages of allowing dose titration if this is desired. The method can be used to treat human beings, in
-particular postmenopausal women in need of such treatment, with an effective osteogenic amount of alendronate to inhibit bone resorption. Such a need arises locally in cases of bone fracture, non-weld deficiency and the like. Such a need also arises in cases of general bone disease, with osteoporosis, osteoarthritis, Paget's disease, osteomalacia disease, multiple myeloma, steroid therapy, loss related to the age of the bone mass. The term "inhibition of bone resorption" as used herein, refers to the treatment and prevention of bone deterioration, especially the inhibition of existing bone removal either from the general phase and / or organic matrix phase, by direct alteration or indirect of osteoclast formation or activity. Thus, the term "bone resorption inhibitor" as used herein refers to people who prevent bone deterioration by directly or indirectly altering the formation or activity of the osteoclasts and which can increase bone mass in the body. the populations of patients in treatment. The term "osteogenic effective entity" as used herein means the amount that the cycle of mature bone performs. As used herein, an osteogenically effective dose is also "pharmaceutically effective". The term "treatment" or "treating" such co or is used herein means (1) providing an individual with an amount of
- alendronate sufficient to act prophylactically and prevent the development of a weakened and / or unhealthy state; I
(2) providing an individual with a sufficient amount of alendronate in order to alleviate or eliminate a morbid condition and / or the symptoms of a morbid state and a weakened and / or unhealthy state. Pharmaceutical formulations of the invention that include alendronate for administration will generally include an osteogenic amount capable of alendronate to promote bone growth, in addition to a pharmaceutically acceptable excipient. The compositions are advantageously prepared together with the dry inert carriers for the powder form such as sugars, including sucrose and lactose, starch and derivatives, cellulose and derivatives, gums, fatty acids and their salts. For liquid formulations, some suitable excipients / liquid carriers are purified water and saline. ^ Other suitable excipients and other accessory additives are the following:
Ethanol solvents glycerin propylene glycol
r ~ Esf, ap, fl ',. | ore. EDTñ (ethylene-diamine-tetraacetic acid)
flqent.com Prpfilág icQS sodium benzoate sorbic acid methyl-p-hydroxy-benzoate propi1-p-hydroxy-benzoate DH Regulators citric acid / sodium citrate tartrate potassium acid tartrate sodium acid phthalate potassium acid phthalate sodium acid phosphate diacid of potassium phosphate sodium acid
Sflt? QrÍz, ap? Es, saccharin lactose sucrose fructose sorbitol aspartame
Viscosity agents derived from cellulose including: hydroxymethyl cellulose hydropropyl cellulose
Colorants Blue FD &C 2 Red FD &C 33 In addition, the presence of a regulator is necessary to maintain the aqueous pH in the range of 2-8 and preferably 4-6. The regulatory system is usually a mixture of a weak acid and a salt thereof, for example sodium citrate / citric acid; or the onocationic or di-cationic salt of a dibasic acid, for example, potassium acid tartrate; sodium acid tartrate, sodium acid phthalate, acid phthalate
-.- of potassium, diacid phosphate of potassium and phosphate acid of disodium. The amount of regulatory system used is dependent on (1) the desired pH, and (2) the amount of alendronate. Generally, an amount of regulator used is 0.5 to 50: 1 mole ratio of the regulator to alendronate of the formulation to maintain a constant pH on the scale of 2 to 9 and generally, 1 to 10 of the mole ratio of the regulator to / -alendronate. A useful regulator is sodium citrate / citric acid on a scale of 5 to 50 mg per ml of sodium citrate at 1 to 15 mg per ml. of citric acid. A complexing agent is also present to prevent the precipitation of alendronate through the formation of metal complexes with dissolved metal ions, for example Ca, Mg, Fe, Al, Ba, which can be extracted by leaching from glass containers or plugs of rubber, or be present in the ordinary water of the tap. The agent acts as a suitable complexing agent with alendronate and produces a soluble metal complex while alendronate usually forms an insoluble metal complex. Complexing agents include citrate regulators, which act as regulatory / complexing agent or EDTA. When EDTA is used, it is used in an amount of 0.005-0.1% by weight of the composition and 0.005-2 parts of EDTA to 1? Part by weight of alendronate and preferably about 0.01% by weight of the composition. It is preferred when only the citrate regulator is used.
Some examples of oral dosage forms of alendronate are: Aqueous Oral Solution The drug alendronate is dissolved in bulk with water or with appropriate solvents until it reaches the desired concentration. Flavoring agents, coloring agents, viscosity agents, prophylactic agents, stabilizers and regulating agents are added as required. The solution is poured into containers for last or single doses.
The aqueous solution is used as it is directly from the bottle.
General Formulation Alendronate 0.5-10.0 g Sodium citrate 5 - 50 rng Citric acid 1 -15 mg Purified water q.s. 1 ml
Additional agents such as co-cosolvents, flavoring agents, coloring agents, prophylactic agents, stabilizers and pH regulating agents in the formulation can also be specifically incorporated as follows:
Formulation Specifies Alendronate 0.5-10.0 mg Sodium citrate 5 - 50 rng Citric acid 1 -15 mg Wild cherry (powder) "10-200 rng Red FDC No. 33" 0.1 -1.0 g,. Sorbic acid 0.05 -0.2% Saccharin c 1 -100 rng Propylene glycol 5 -20% Purified water q.s. 1 ml
• Flavors other than wild cherry may also be used. Other colorants other than FDC No. 33 can also be chosen to match other flavors. c Sucrose or aspartame can be used alternatively to sweeten.
Jsrsbe QG = ÍI The drug alendronate is incorporated in bulk in the sucrose solution (10-85%) until reaching the desired concentration. Additional agents are added such as glycerin, eorbitol, flavoring agents, coloring agents, candidity agents, prophylactic agents,
- stabilizers, and regulatory agents as required. The final solution is poured into envaeee for multiple or unit doses.
The syrup can be used as it is directly from the bottle or it can be added to a small amount of tap water to facilitate its swallowing.
- General Formulation Alendronate 0. 5-10 .0 rng Citric acid 1 - 15mg Sodium citrate 5-50 mg Sucrose 10 - 85% Purified water q. s. 1 rnl
Additional agents such as glycerin, sorbitol, flavoring agents, coloring agents, viscosity agents, prophylactic agents, stabilizing agents and regulating agents can also be incorporated specifically in the formulation as follows:
Formulation Alendronate 0.5-10.0 ng Citric acid 1 - 15mg Sodium citrate 5 - 50 rng Glycerin 5 - 25% Sucrose 10 - 40% Sorbitol 10 - 40% Wild cherry (powder) 4 »10 - 200rng Red FDC No. SS * »0.1 - 1.0 mg Sorbic acid 0.05 - 0.2% Purified water qs 1 ml
• You can also use flavors that are not wild cherry. * > Other colorants other than FDC No. 33 can also be chosen to match other flavors.
Powder for use Mix alendronate in bulk until homogeneous with one or more of the following: flavoring agents, coloring agents, prophylactic agents, stabilizers and specifically with a regulating agent. The powder mixture is then poured into multi-dose containers or unit dose packs.
The powder can be dissolved in ordinary tap water to reconstitute the alendronate in aqueous solution.
Nara powder formulation Reconsti uci n Amount per container for unit dose: "*
ñlendronate 2 - 50 mg Sucrose 100 - 1000 rng Sodium Citrate 25 - 500 rng Citric acid 5 - 500 rng
"The package can be a bottle (to which water is added) or a perfume bag, Alternatively, the bulk formulation can be provided in a multi-dose container.
The precise dose needed will vary with the age, stature, eexo and condition of the individual, the nature and seriousness of the disorder to be treated and other similar aspects; This way you can not specify an accurate effective amount in advance and it will be determined by the person-in-charge. However, appropriate amounts can be determined by routine experimentation with animal models, as described below. In general terms, an effective dose of alendronate in any one of the lae liqee orlealcee oralee is about 1.5 to 3000 μg / kg of body weight and preferably and about
μg / kg to approximately 200 μg / kg of body weight.
The methods and compositions of the invention are useful for treating bone fractures, deficiencies and disorders resulting from pathological conditions of osteoporosis, osteoarthritis, Paget's disease, osteohalisteresis, osteomalacia, bone deterioration resulting from multiple myeloma and other forms of cancer. , bone deterioration resulting from side effects of other medical treatments (such as steroids), and loss related to the age of the bone mass.
Claims (25)
1. - A pharmaceutical composition comprising a pharmaceutically effective amount of alendronate, in a pharmaceutically acceptable carrier and a sufficient amount of a regulator to maintain a pH of the composition in the range of 2 to 8 and a complexing agent to prevent precipitation of the alendronate in the aqueous solution.
2. The pharmaceutical composition of claim 2 which constitutes a liquid.
3. The pharmaceutical composition of claim 3, characterized in that said liquid is a syrup.
4. The pharmaceutical composition of claim 2, characterized in that said liquid is an aqueous solution.
5. The pharmaceutical composition of claim 1 which constitutes a powder for reconstitution. 6.- The pharmaceutical composition of the claim 5 dissolved in water. 7. The pharmaceutical composition of the claim 1, characterized in that said alendronate is present in the amount of 0.0005 to 0.5 grams per gram of composition. 8. The pharmaceutical composition of the claim 1, characterized in that said pharmaceutically acceptable excipient is purified water. 9. The pharmaceutical composition of the claim 1, characterized in that said regulator is sodium citrate / citric acid, potassium acid tartrate, eodium acid tartrate, potassium diacid phosphate and disodium acid phosphate. 10. The pharmaceutical composition of claim 1, characterized in that said regulator is present in an amount of 0.5 to 50: 1 according to the mol ratio of the regulator to alendronate. 11. The pharmaceutical composition of claim 1, characterized in that said complexing agent is EDTñ. 12. The pharmaceutical composition of claim 11, characterized in that said EDTA is present in a ratio of 0.0005-2: 1 parts by weight per part of alendronate by weight. 13. The pharmaceutical composition of claim 1, characterized in that said pH is in the range of 4-
6. 14. The pharmaceutical composition of the claim 1 constituting a syrup of the following formula: alendronate, 0.5-10.0 mg; citric acid, 1-15 rng; sodium citrate, 5-50 mg; sucrose, 10-85%; purified water, q.s. 1 L. 15. A pharmaceutical composition of claim 14 which constitutes a syrup of the following formula: alendronate, 0.5-10.0 rng; citric acid, 1-15 g; Sodium citrate, 5-50 mg; glycerin, 5-25%; sucrose, 10-40%; sorbitol, 10-40%; Wild cherry (powder), 10-200 mg; red FDC No. 33, 0.1-1.0 g; sorbic acid, 0.05-0.2%; purified water, q.s. 1 rnL. 16.- The pharmaceutical composition of the claim 1, which constitutes an aqueous solution of the following formula: alendronate, 0.5-10.0 mg; sodium citrate, 5-50 mg; citric acid, 1-15 mg; purified water, q.s. 1 mL 1
7. The pharmaceutical composition of claim 16 having the formula: alendronate, 0.5-10.0 mg; sodium citrate, 5-50 g; citric acid, 1-15 mg; wild cherry (powder), 10-200 g; red FDC No. 33, 0.1-1.0 mg; sorbic acid, 0.05-0.2%; saccharin, 1-100 g; propylene glycol, 5-20%; purified water, q.s. 1 rnL. 1
8. The pharmaceutical composition of the claim 1, which constitutes a powder for reconstitution of the following formula: alendronate, 2-50 g; sacaroea, 100-1000 mg; sodium citrate, 25-500 mg; citric acid, 5-500 rng. 1
9. A method for treating and / or preventing bone deterioration in an individual having difficulty swallowing, which consists of administering a pharmaceutically effective dose of an oral liquid containing the pharmaceutical composition alendronate as defined in claim 1. The method of claim 19, characterized in that said individual is a human being. 21. The method of claim 19, characterized in that the bone deterioration is related to osteoporosis, due to the age-related delay, related to the therapy based on steriodes., related to rheumatism, related to Paget's disease, or related to cancer. 22. The method of claim 19, characterized in that the treatment is prophylactic. 23. The method of claim 19, characterized in that said liquid is a syrup. 24. The method of claim 19, characterized in that said liquid is an aqueous solution. 25. The method of claim 19, characterized in that said liquid is an aqueous solution formed from a powder for reconsti- tion. BESUBEtl A therapy protocol is described for treating and preventing bone deterioration in patients having difficulty swallowing, by administering a liquid formulation of alendronate which can be easily digested. Also described are pharmaceutical dosage forms of a syrup, an aqueous solution, a solution formed of a / reconstituted powder, alendronate, to carry out the therapeutic method. GC / yhc * cprn P96-823F
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08245289 | 1994-05-17 | ||
| US08/245,289 US5462932A (en) | 1994-05-17 | 1994-05-17 | Oral liquid alendronate formulations |
| PCT/US1995/005926 WO1995031203A1 (en) | 1994-05-17 | 1995-05-12 | Oral liquid alendronate formulations |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MXPA96005660A true MXPA96005660A (en) | 1998-02-01 |
| MX9605660A MX9605660A (en) | 1998-02-28 |
Family
ID=22926074
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX9605660A MX9605660A (en) | 1994-05-17 | 1995-05-12 | Oral liquid alendronate formulations. |
Country Status (34)
| Country | Link |
|---|---|
| US (1) | US5462932A (en) |
| EP (1) | EP0759757B1 (en) |
| JP (1) | JP4111536B2 (en) |
| KR (1) | KR100372966B1 (en) |
| CN (1) | CN1079672C (en) |
| AT (1) | ATE222495T1 (en) |
| AU (1) | AU691634B2 (en) |
| CA (1) | CA2190148C (en) |
| CO (1) | CO4600739A1 (en) |
| CY (1) | CY2336B1 (en) |
| CZ (1) | CZ285860B6 (en) |
| DE (1) | DE69527842T2 (en) |
| DK (1) | DK0759757T3 (en) |
| DZ (1) | DZ1884A1 (en) |
| ES (1) | ES2180646T3 (en) |
| FI (1) | FI118296B (en) |
| HK (1) | HK1009245A1 (en) |
| HR (1) | HRP950293B1 (en) |
| HU (1) | HU220626B1 (en) |
| IL (1) | IL113651A (en) |
| MX (1) | MX9605660A (en) |
| MY (1) | MY112285A (en) |
| NO (1) | NO310179B1 (en) |
| NZ (1) | NZ289231A (en) |
| PL (1) | PL179634B1 (en) |
| PT (1) | PT759757E (en) |
| RU (1) | RU2176507C2 (en) |
| SI (1) | SI0759757T1 (en) |
| SK (1) | SK281098B6 (en) |
| TW (1) | TW402501B (en) |
| UA (1) | UA29505C2 (en) |
| WO (1) | WO1995031203A1 (en) |
| YU (1) | YU49354B (en) |
| ZA (1) | ZA953960B (en) |
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-
1994
- 1994-05-17 US US08/245,289 patent/US5462932A/en not_active Expired - Lifetime
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1995
- 1995-05-08 IL IL11365195A patent/IL113651A/en not_active IP Right Cessation
- 1995-05-09 TW TW084104572A patent/TW402501B/en not_active IP Right Cessation
- 1995-05-11 MY MYPI95001236A patent/MY112285A/en unknown
- 1995-05-12 HU HU9603162A patent/HU220626B1/en not_active IP Right Cessation
- 1995-05-12 DE DE69527842T patent/DE69527842T2/en not_active Expired - Lifetime
- 1995-05-12 WO PCT/US1995/005926 patent/WO1995031203A1/en active IP Right Grant
- 1995-05-12 JP JP52977395A patent/JP4111536B2/en not_active Expired - Fee Related
- 1995-05-12 AT AT95924570T patent/ATE222495T1/en active
- 1995-05-12 CZ CZ963367A patent/CZ285860B6/en not_active IP Right Cessation
- 1995-05-12 SI SI9530610T patent/SI0759757T1/en unknown
- 1995-05-12 UA UA96124659A patent/UA29505C2/en unknown
- 1995-05-12 MX MX9605660A patent/MX9605660A/en unknown
- 1995-05-12 NZ NZ289231A patent/NZ289231A/en unknown
- 1995-05-12 CA CA002190148A patent/CA2190148C/en not_active Expired - Fee Related
- 1995-05-12 DK DK95924570T patent/DK0759757T3/en active
- 1995-05-12 KR KR1019960706447A patent/KR100372966B1/en not_active IP Right Cessation
- 1995-05-12 PL PL95320614A patent/PL179634B1/en not_active IP Right Cessation
- 1995-05-12 CN CN95193086A patent/CN1079672C/en not_active Expired - Fee Related
- 1995-05-12 AU AU29010/95A patent/AU691634B2/en not_active Expired
- 1995-05-12 EP EP95924570A patent/EP0759757B1/en not_active Expired - Lifetime
- 1995-05-12 PT PT95924570T patent/PT759757E/en unknown
- 1995-05-12 SK SK1477-96A patent/SK281098B6/en unknown
- 1995-05-12 RU RU96123917/14A patent/RU2176507C2/en not_active IP Right Cessation
- 1995-05-12 ES ES95924570T patent/ES2180646T3/en not_active Expired - Lifetime
- 1995-05-16 CO CO95020682A patent/CO4600739A1/en unknown
- 1995-05-16 ZA ZA953960A patent/ZA953960B/en unknown
- 1995-05-16 HR HR950293A patent/HRP950293B1/en not_active IP Right Cessation
- 1995-05-16 DZ DZ950055A patent/DZ1884A1/en active
- 1995-05-17 YU YU31795A patent/YU49354B/en unknown
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1996
- 1996-11-15 FI FI964593A patent/FI118296B/en not_active IP Right Cessation
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1998
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