US20020001598A1 - Pharmaceutical microspheres containing valproic acid for oral administration - Google Patents
Pharmaceutical microspheres containing valproic acid for oral administration Download PDFInfo
- Publication number
- US20020001598A1 US20020001598A1 US09/147,788 US14778899A US2002001598A1 US 20020001598 A1 US20020001598 A1 US 20020001598A1 US 14778899 A US14778899 A US 14778899A US 2002001598 A1 US2002001598 A1 US 2002001598A1
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- United States
- Prior art keywords
- pharmaceutical
- microspheres according
- valproic acid
- weight
- microspheres
- Prior art date
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- NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 title claims abstract description 102
- 239000004005 microsphere Substances 0.000 title claims abstract description 93
- 229960000604 valproic acid Drugs 0.000 title claims abstract description 59
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 claims abstract description 58
- 239000000203 mixture Substances 0.000 claims abstract description 57
- 239000011159 matrix material Substances 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 239000003981 vehicle Substances 0.000 claims abstract description 19
- 239000001993 wax Substances 0.000 claims abstract description 12
- 239000003921 oil Substances 0.000 claims abstract description 8
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 7
- 150000002314 glycerols Chemical class 0.000 claims abstract description 6
- -1 alkali metal salt Chemical class 0.000 claims description 20
- 235000013871 bee wax Nutrition 0.000 claims description 18
- 239000012166 beeswax Substances 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 10
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 9
- 238000002844 melting Methods 0.000 claims description 9
- 230000008018 melting Effects 0.000 claims description 9
- 125000005456 glyceride group Chemical group 0.000 claims description 8
- 239000012188 paraffin wax Substances 0.000 claims description 8
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 239000004359 castor oil Substances 0.000 claims description 6
- 235000019438 castor oil Nutrition 0.000 claims description 6
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- DMBUODUULYCPAK-UHFFFAOYSA-N 1,3-bis(docosanoyloxy)propan-2-yl docosanoate Chemical group CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCCCCCC DMBUODUULYCPAK-UHFFFAOYSA-N 0.000 claims description 5
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 claims description 4
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 150000005690 diesters Chemical class 0.000 claims description 4
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 4
- 229940075529 glyceryl stearate Drugs 0.000 claims description 4
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 4
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 claims description 4
- 159000000000 sodium salts Chemical class 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- QHZLMUACJMDIAE-UHFFFAOYSA-N 1-monopalmitoylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)CO QHZLMUACJMDIAE-UHFFFAOYSA-N 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000012530 fluid Substances 0.000 claims description 3
- 229940096898 glyceryl palmitate Drugs 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 235000003599 food sweetener Nutrition 0.000 claims description 2
- 239000007903 gelatin capsule Substances 0.000 claims description 2
- 230000005484 gravity Effects 0.000 claims description 2
- 239000011256 inorganic filler Substances 0.000 claims description 2
- 229910003475 inorganic filler Inorganic materials 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 159000000003 magnesium salts Chemical class 0.000 claims description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 150000004671 saturated fatty acids Chemical class 0.000 claims description 2
- 239000003765 sweetening agent Substances 0.000 claims description 2
- 150000005691 triesters Chemical class 0.000 claims description 2
- 235000021122 unsaturated fatty acids Nutrition 0.000 claims description 2
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 42
- 229940084026 sodium valproate Drugs 0.000 description 42
- 239000000546 pharmaceutical excipient Substances 0.000 description 22
- 241001440269 Cutina Species 0.000 description 21
- 239000004480 active ingredient Substances 0.000 description 15
- 238000004090 dissolution Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 239000002671 adjuvant Substances 0.000 description 7
- 238000007922 dissolution test Methods 0.000 description 7
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 230000003111 delayed effect Effects 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 description 5
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 5
- 230000002209 hydrophobic effect Effects 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- 235000013618 yogurt Nutrition 0.000 description 5
- 235000021355 Stearic acid Nutrition 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 4
- 239000008117 stearic acid Substances 0.000 description 4
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 4
- 229940102566 valproate Drugs 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 239000007765 cera alba Substances 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000000873 masking effect Effects 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 235000019640 taste Nutrition 0.000 description 2
- 229960000278 theophylline Drugs 0.000 description 2
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 2
- 108010011485 Aspartame Proteins 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N CC(C)C(=O)O Chemical compound CC(C)C(=O)O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 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 1
- 229960003438 aspartame Drugs 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
Images
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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
Definitions
- the present invention generally relates to new pharmaceutical microspheres for oral administration.
- the invention relates to new phamaceutical microspheres for oral administration containing valproic acid of formula:
- alkali metal such as sodium or potassium
- alkaline-earth metal such as calcium or magnesium
- Sodium valproate is an anti-epileptic medicament widely sold at the current time, in particular in the form of tablets assaying 500 mg per administration unit.
- sodium valproate has a rather unpleasant, bitter taste. It will consequently prove to be necessary to take into account this disadvantage in administration forms suitable for children, for example syrup forms or solutions to be taken orally, by masking this taste using various expedients.
- administration forms such as syrups do not allow children to benefit from the advantages resulting in some cases from the gastroresistance and the prolonged release of the active ingredient.
- microsphere pharmaceutical form lends itself poorly to sustained release of the active ingredient. This is because, for equal masses, the surface area developed by these spheres will increase as their diameter becomes smaller, the consequence of which will be that these microspheres dissolve faster.
- the spherical particle formed by dispersion solidify as microspheres.
- the mean concentration of valproic acid in these microspheres does not exceed 17%, these microspheres having a certain concentration of the surfactant used, namely a mixture of ethoxylated or non-ethoxylated polysorbates.
- Another technique for forming pharmaceutical microspheres resorts to the prilling technique.
- This process has been applied, for example, to pharmaceutical ingredients with an undefined crystallization point which melt in the excipient, as described in Patent EP 438,350.
- This excipient can be, for example, a fatty alcohol, such as stearyl alcohol, a fatty acid, such as stearic acid, a glycerol ester, a hydrogenated oil, a fatty acid salt, a polyol, a wax, a polyoxyethylene glycol or an esterified polyoxyethylene.
- stearic acid is exemplified therein as excipient.
- ketoprofen fatty acids and their salts, glycerol esters, hydrogenated oils, waxes or esterified polyoxyethylenes alone can be used.
- microspheres In the majority of cases, these microspheres have additionally turned out to be suitable for sustained release of the active ingredient, without requiring them to be provided with a specific coating for this purpose.
- a first subject of the invention relates to pharmaceutical microspheres containing, as active principle, a mixture of valproic acid and of one of its pharmaceutically acceptable salts, such as the sodium salt, in combination with a matrix vehicle selected from glycerol esters, hydrogenated oils, esterified polyethylene glycols, waxes and their mixtures.
- a matrix vehicle selected from glycerol esters, hydrogenated oils, esterified polyethylene glycols, waxes and their mixtures.
- Another subject of the invention relates to a process for the preparation of microspheres containing a mixture of valproic acid and of a pharmaceutically acceptable salt of this acid, in combination with a matrix vehicle.
- the invention relates to a pharmaceutical form for oral administration containing microspheres according to the invention.
- active principle will denote the mixture of valproic acid and of pharmaceutically acceptable salt of this acid used in the context of the present invention.
- microspheres of the invention can be obtained according to the prilling process mentioned above, which consists:
- a fluidized bed can be added to this prilling tower, which bed makes it possible to keep the not yet completely solidified microspheres constantly fluidized.
- the mixture used in the prilling can be obtained by heating the matrix vehicle to its melting temperature, then, when the mass is completely molten, by adding valproic acid and then a pharmaceutically acceptable salt of this acid, and by maintaining the combined mixture with stirring until a clear fluid is obtained.
- microspheres of the invention contain, as active principle, a mixture in all proportions of valproic acid and of one of its pharmaceutically acceptable salts.
- This salt is generally an alkali metal salt, preferably the sodium salt, or an alkaline-earth metal salt, such as the calcium or magnesium salt.
- the active principle is composed of mixtures of 15% to 60% by weight of valproic acid and of 40% to 85% by weight of pharmaceutically acceptable salt of this acid.
- Mixtures containing from 25% to 35% by weight of valproic acid and from 65% to 75% by weight of the salt in question represent mixtures which are particularly preferred for the purposes of the invention.
- the viscosity of the composition formed by the pharmaceutical ingredient and the matrix excipient is a limiting factor in making use of the prilling process suited to the preparation of pharmaceutical microspheres.
- the microspheres of the invention will contain at most 35% by weight of active principle, as described above, preferably from 30% to 35% by weight.
- This matrix vehicle which is composed of one or of several excipients of the class of glycerol esters, hydrogenated oils, esterified polyethylene glycols, or waxes, is selected such that its melting point is between 50° C. and 120° C., generally between 70° C. and 90° C.
- This matrix vehicle does not contain any additional contribution of surface-active agents, such as those of the ethoxylated or non-ethoxylated polysorbate type.
- Excipients capable of melting at a temperature of the order of 80° C. are preferably selected. Moreover, an excessively high temperature would require an excessively high drop height for the microspheres in order to achieve complete solidification, with the risk of causing the active principle to degrade.
- the excipients in question can be selected from:
- saturated or unsaturated fatty acid glycerides in particular glycerides containing up to 80 carbon atoms, such as, for example, glyceryl tribehenate, glyceryl palmitate/stearate, glyceryl monostearate, glyceryl monooleate or caprylic/capric glycerides, such as glyceryl tricaprylate/caprate
- saturated polyglycolysed glycerides such as mixtures of glycerol monoesters, diesters and triesters and of polyethylene glycol mono- and diesters
- hydrogenated oils such as hydrogenated castor oil
- a wax such as natural beeswax or synthetic beeswax.
- matrix excipients capable of forming microspheres according to the invention can be selected from:
- glyceryl tribehenate such as sold under the trademark Compritol® 888
- glyceryl palmitate/stearate such as sold under the trademark Precirol® ATO5
- glyceryl monostearate such as sold under the trademark Monomuls® 90/25
- glyceryl monooleate such as sold under the trademark Myverol® 18/99
- glyceryl tricaprylate/caprate such as sold under the trademark Labrafac® lipophile
- saturated polyglycolysed glycerides such as sold under the trademarks Gelucire® 50-02 or Labrafil® 2130CS
- excipients used in the context of the invention will furthermore be selected while taking into account the hydrophilic, lipophilic (or hydrophobic) or amphiphilic nature which they may possess and according to the kinetics desired for the release of the active principle.
- mixtures of excipients of the type either glyceryl tribehenate (Compritol® 888)/surfactant (Labrafil® 2130CS) or glyceryl tribehenate (Compritol® 888)/glyceryl monooleate (Myverol® 18/99) or synthetic beeswax (Cutina® BW)/hydrogenated castor oil (Cutina® HR)/glyceryl monostearate (Monomuls® 90/25) have proved to be suitable for fairly immediate release of the active principle.
- Microspheres comprising from 55% to 60% by weight of product Compritol® 888 or of product Precirol® ATO5, from 30% to 35% by weight of active principle (valproic acid/sodium valproate) and from 10% to 15% by weight of surfactant Labrafil® 2130CS were used for this purpose.
- hydrophobic substances such as hydrogenated castor oil (Cutina® HR), beeswax, paraffin, the product Gelucire® 50-02 or the product Labrafac® lipophile, has furthermore made it possible to accentuate the delayed release of the active principle.
- Cutina® HR hydrogenated castor oil
- beeswax paraffin
- paraffin the product Gelucire® 50-02
- microspheres containing from 65 to 70% by weight of the product Compritol® 888 and from 30% to 35% by weight of active principle have revealed, during dissolution tests, a slow dissolution profile.
- Analogous results were recorded from microspheres comprising from 55% to 60% by weight of the product Compritol® 888, 10% to 15% by weight of the product Cutina® HR, beeswax, paraffin, the product Gelucire® 50-02 or the product Labrafac® lipophile and 30% to 35 by weight of active principle.
- the active principle used in the present invention is composed of a hydrophobic component, namely valproic acid, and of a hydrophilic component, that is to say a pharmaceutically acceptable salt of this acid, it seems that the most suitable matrix excipients should be amphiphilic substances, in order, by their hydrophobic part, to provide for the delayed release of the active principle and, by their hydrophilic part, to provide for the regulation of the rate of release of this active principle from the excipient.
- composition A microspheres formed of 68.37 g of natural beeswax as matrix vehicle and of 31.63 g of active principle, namely 9.63 g of valproic acid and 22 g of sodium valproate, hereinafter denoted “Composition A microspheres”.
- the active principle consequently corresponds to a 30.45%/69.55% by weight valproic acid/sodium valproate mixture.
- a divisible retard tablet formulated with 478 mg of a valproic acid/sodium valproate mixture, namely 145 mg of acid and 333 mg of salt, this tablet comprising in particular methacrylic acid polymers as excipient.
- the active ingredients of this commercial tablet-consequently correspond to a 30.33%/69.67% by weight valproic acid/sodium valproate mixture or to 500 mg of active ingredient expressed as sodium valproate.
- microspheres represents the percentages of dissolution of the valproate anion as a function of the time from the above Composition
- a divisible retard tablet such as above so that each subject receives a dose of active ingredient (valproic acid/sodium valproate) equivalent to 500 mg expressed as sodium valproate.
- composition A/water represents the mean blood concentration obtained with the Composition A microspheres in water
- composition A/yoghurt represents the mean blood concentration obtained with the Composition A microspheres in yoghurt
- microspheres containing from 30% to 35% of active principle in combination with a matrix vehicle entirely composed of beeswax represent microspheres of vital importance.
- microspheres of this type in which the active principle is formed of 25% to 35% of valproic acid and of 65% to 75% of a pharmaceutically acceptable salt of this acid, such as sodium valproate, are particularly preferred for the purposes of the invention.
- prilling makes it possible to obtain a so-called monodisperse particle size distribution with the advantage of producing spheres which are regular in size. Consequently, during the administration of the medicament containing them, the amount of such microspheres received by the patient will be constant.
- the pharmaceutical microspheres of the invention possess this advantage, in that they exhibit such a regular spherical shape, with a diameter of between 250 ⁇ m and 500 ⁇ m, generally of the order of 400 ⁇ m.
- these microspheres can be covered with a film-forming agent, so as to form, for example, a gastroresistant film.
- Such pharmaceutical forms can be, for example, a tablet, including a divisible tablet, a capsule, including a hard gelatin capsule, or a powder packaged, for example, in a chartula or in a system for dispensing unit doses, in particular a dispensing/measuring bottle or a container furnished with an adjustable-volume measuring spoon, for example for adjusting doses to the weight of the patient.
- the microspheres in question can receive agents which facilitate flow, as well as lubricants, inorganic fillers, such as silicas, talc or aluminium oxide, or alternatively sweeteners, such as aspartame.
- These pharmaceutical forms can advantageously comprise, per administration unit, from 50 to 500 mg of active principle in the form of microspheres according to the invention, in particular from 50 to 250 mg.
- Microspheres with the following composition are prepared: % by weight White beeswax 68.424 Valproic acid 9.576 Sodium valproate 22 100.00
- 68.424 g of white beeswax are introduced into the jacketed vessel of a melting device thermostatically adjusted to 95° C. and then the wax is melted at a temperature of 90° C. to 93° C. while monitoring that the product has completely melted.
- the mixture is then prilled, at a temperature of 90° C., through 200 ⁇ m injectors maintained at a temperature of 87° C. to 91° C. and under a pressure of 0.5 bar.
- the frequency of the vibrator of the device (5.75 ⁇ 10 3 to 6.70 ⁇ 10 3 Hz) is adjusted, so as to individualize the droplets formed, under stroboscopic monitoring at a frequency of 25,000 Hz.
- Microspheres solidified by cooling during their fall in air (drop height: approximately 2.5 m) refrigerated by a countercurrent of cold air or by a liquid nitrogen bath are thus collected at the base of the device. These microspheres have a mean diameter of 400 ⁇ m.
- Microspheres were prepared in the same way, but by using other matrix excipients, from the following formulations, which all proved to be clear after dissolution of the active principle (rig appearance Of crystals):
- Example 1 756.7 mg of microspheres as prepared in Example 1 are introduced into a chartula, so as to form an oral administration unit containing 238.96 mg of active principle composed of 30.4%/ 69 . 6 % by weight valproic acid/sodium valproate, which corresponds to 250 mg of active principle expressed as sodium valproate.
- microspheres prepared in Example 1 i.e. 8 g of active principle per packaged unit, are introduced into a bottle with a working volume of approximately 45 ml which allows unit doses to be dispensed.
- This bottle makes it possible to dispense approximately 50 unit doses containing 150 mg of active principle composed of 30.4%/69.6% by weight valproic acid/sodium valproate.
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Abstract
Description
- The present invention generally relates to new pharmaceutical microspheres for oral administration.
-
- and one of its pharmaceutically acceptable salts, in particular an alkali metal, such as sodium or potassium, or alkaline-earth metal, such as calcium or magnesium, salt.
- Sodium valproate is an anti-epileptic medicament widely sold at the current time, in particular in the form of tablets assaying 500 mg per administration unit.
- These tablets, which are provided with an enteric or programmed-release coating, are for this reason fairly large.
- In consequence, such tablets will generally be disadvantageous, in particular for children or people experiencing difficulties in swallowing, for example elderly people.
- For this type of patient, it thus appears desirable to have available administration forms which are better suited to their state or to their condition.
- Moreover, sodium valproate has a rather unpleasant, bitter taste. It will consequently prove to be necessary to take into account this disadvantage in administration forms suitable for children, for example syrup forms or solutions to be taken orally, by masking this taste using various expedients.
- However, administration forms such as syrups do not allow children to benefit from the advantages resulting in some cases from the gastroresistance and the prolonged release of the active ingredient.
- Moreover, the adjustment of the dose of active ingredient to the weight of the child, the child posology per kg of body weight being observed, represents an additional constraint in paediatrics.
- A few years ago, a new pharmaceutical dosage presentation appeared which makes it possible to satisfy some of these requirements. It consists of a fine semolina composed of microspheres, in which microspheres the active ingredient is most often covered with an isolating film. This fine semolina, sprinkled over a spoonful of semi-solid food, for example puree, compote or yoghurt, is administered as is.
- However, the so-called microsphere pharmaceutical form lends itself poorly to sustained release of the active ingredient. This is because, for equal masses, the surface area developed by these spheres will increase as their diameter becomes smaller, the consequence of which will be that these microspheres dissolve faster.
- In order to overcome this disadvantage, it will generally be recommended to provide these spheres with an appropriate coating which makes possible the desired delayed release.
- While it is industrially possible to coat pharmaceutical microspheres, it is however lengthy because it requires a large amount of polymer to be deposited.
- Various methods for manufacturing these microspheres, sometimes known as “prills”, are known and have been experimented with for various active ingredients.
- One of them, applied to valproic acid, has been described in “Drug Development and Industrial Pharmacy”, 21(7), pp. 793-807 (1995).
- According to this process, a mixture composed of white beeswax in the molten form, valproic acid and a surface-active agent is stirred in an aqueous medium at pH=4.5 while maintaining the mixture at a temperature greater than the melting temperature of the wax. On cooling, the spherical particle formed by dispersion solidify as microspheres.
- However, the mean concentration of valproic acid in these microspheres does not exceed 17%, these microspheres having a certain concentration of the surfactant used, namely a mixture of ethoxylated or non-ethoxylated polysorbates.
- Another technique for forming pharmaceutical microspheres resorts to the prilling technique.
- According to this technique, described in particular in Patent DE 2,725,924, an excipient, the melting point of which is less than 120° C., is melted, the dissolved or dispersed active ingredient can be added thereto and then this molten dispersion is passed through a vibrating nozzle which causes the jet to break up and spherical droplets to form, which cool as microspheres in falling.
- This process has been applied, for example, to pharmaceutical ingredients with an undefined crystallization point which melt in the excipient, as described in Patent EP 438,350. This excipient can be, for example, a fatty alcohol, such as stearyl alcohol, a fatty acid, such as stearic acid, a glycerol ester, a hydrogenated oil, a fatty acid salt, a polyol, a wax, a polyoxyethylene glycol or an esterified polyoxyethylene. Moreover, stearic acid is exemplified therein as excipient.
- However, it was specified therein that, in the specific case of ketoprofen, fatty acids and their salts, glycerol esters, hydrogenated oils, waxes or esterified polyoxyethylenes alone can be used.
- Other pharmaceutical ingredients have also been experimented with in the prilling technique.
- Thus, tests on the manufacture of microspheres containing theophylline as active ingredient have been reported in the “Technical Bulletin”, No. 83, pp 33-47 (1990) of the company Gattefosse, use being made, as matrix excipient, of combinations such as stearic acid/white wax or carnauba wax/glyceryl stearate (Precirol® WL 2155), optionally with addition of saturated polyglycolysed glyceride (Gelucire 50-13), while taking into account the characteristics of these excipients with the process chosen.
- However, problems of homogeneity were recorded which resulted, according to this publication, in so-called wax mixtures being abandoned for the formation of theophylline microspheres.
- In the context of the present invention, attempts were made to apply this technique to sodium valproate. However, the first tests carried out, starting with a matrix comprising a stearic derivative, demonstrated a number of problems, including crystallization of the sodium valproate in the mixture subjected to prilling and a viscosity unsuitable for the manufacture of microspheres.
- These disadvantages were displayed in particular during the use of a 68/2/30 by weight mixture of stearyl alcohol/Gelucire® 50-13/sodium valproate.
- Moreover, tests making use of sodium valproate and stearic acid as excipient showed a high degree of incompatibility, since precipitation brought about by contact of these ingredients is recorded.
- It consequently appears illusory to transpose to sodium valproate the matrix excipients commonly used in the prior art for the preparation of pharmaceutical microspheres by the prilling technique.
- In addition, the fruitless tests reported, on the one hand, in the state of the art and, on the other hand, in the context of the present invention convincingly show that there does not exist a standard excipient which can be employed in a prilling process whatever the active pharmaceutical ingredient used.
- Consequently, the development of an administration form for sodium valproate which is simultaneously easy to use in paediatrics and geriatrics, capable of masking the unpleasant taste of this active ingredient and preferentially possesses a sustained-release profile remains of undeniable interest.
- It has now been found, surprisingly, that it is possible to avoid the disadvantages reported above by using, as administration form, microspheres containing, as active ingredient, sodium valproate or any other pharmaceutically acceptable salt of valproic acid and valproic acid itself, in combination with a suitably chosen matrix vehicle.
- In the majority of cases, these microspheres have additionally turned out to be suitable for sustained release of the active ingredient, without requiring them to be provided with a specific coating for this purpose.
- Thus, a first subject of the invention relates to pharmaceutical microspheres containing, as active principle, a mixture of valproic acid and of one of its pharmaceutically acceptable salts, such as the sodium salt, in combination with a matrix vehicle selected from glycerol esters, hydrogenated oils, esterified polyethylene glycols, waxes and their mixtures.
- Another subject of the invention relates to a process for the preparation of microspheres containing a mixture of valproic acid and of a pharmaceutically acceptable salt of this acid, in combination with a matrix vehicle.
- Finally, the invention relates to a pharmaceutical form for oral administration containing microspheres according to the invention.
- In the present context, both in the description and in the claims, “active principle” will denote the mixture of valproic acid and of pharmaceutically acceptable salt of this acid used in the context of the present invention.
- The microspheres of the invention can be obtained according to the prilling process mentioned above, which consists:
- in adding valproic acid and the pharmaceutically acceptable salt of this acid to the matrix vehicle in the molten form, so as to dissolve these active ingredients in the matrix, and maintaining A, the resulting mixture with stirring until a clear fluid is obtained,
- in forcing the mixture in the clear form thus obtained through a nozzle which is subjected to vibration, whereby droplets are formed at the outlet of the nozzle and are carried by gravity into a tower in which a cold gas, generally refrigerated air, moves in a counter-currentwise direction,
- in collecting the microspheres in the bottom of the tower.
- If necessary, a fluidized bed can be added to this prilling tower, which bed makes it possible to keep the not yet completely solidified microspheres constantly fluidized.
- In practice, the mixture used in the prilling can be obtained by heating the matrix vehicle to its melting temperature, then, when the mass is completely molten, by adding valproic acid and then a pharmaceutically acceptable salt of this acid, and by maintaining the combined mixture with stirring until a clear fluid is obtained.
- Alternatively, it is also possible to prepare this mixture by adding, separately, the pharmaceutically acceptable salt of valproic acid to valproic acid itself and by then introducing the combined mixture into the molten matrix vehicle.
- The microspheres of the invention contain, as active principle, a mixture in all proportions of valproic acid and of one of its pharmaceutically acceptable salts.
- This salt is generally an alkali metal salt, preferably the sodium salt, or an alkaline-earth metal salt, such as the calcium or magnesium salt.
- Preferentially, but not exclusively, use is made as active principle of mixtures containing at least 5% by weight either of valproic acid or of one of its pharmaceutically acceptable salts, the surplus being composed of at most 95% by weight of a pharmaceutically acceptable salt of valproic acid or of valproic acid respectively.
- In particular, the active principle is composed of mixtures of 15% to 60% by weight of valproic acid and of 40% to 85% by weight of pharmaceutically acceptable salt of this acid.
- Mixtures containing from 25% to 35% by weight of valproic acid and from 65% to 75% by weight of the salt in question represent mixtures which are particularly preferred for the purposes of the invention.
- As a general rule, the viscosity of the composition formed by the pharmaceutical ingredient and the matrix excipient is a limiting factor in making use of the prilling process suited to the preparation of pharmaceutical microspheres.
- In the present case and for this reason, the microspheres of the invention will contain at most 35% by weight of active principle, as described above, preferably from 30% to 35% by weight.
- Indeed, it has been noticed that a concentration by weight of active principle greater than 35% would require a higher temperature of the matrix mass in order to maintain a sufficient viscosity of the latter for the purpose of preparing the microspheres. Moreover, a concentration of active principle greater than 35% causes difficulties of dissolution of the latter in the matrix vehicle.
- This matrix vehicle, which is composed of one or of several excipients of the class of glycerol esters, hydrogenated oils, esterified polyethylene glycols, or waxes, is selected such that its melting point is between 50° C. and 120° C., generally between 70° C. and 90° C.
- This matrix vehicle does not contain any additional contribution of surface-active agents, such as those of the ethoxylated or non-ethoxylated polysorbate type.
- Excipients capable of melting at a temperature of the order of 80° C., the latter corresponding to the temperature which allows the active principle to be dissolved in the matrix vehicle and to the maximum temperature which can be used for good preservation of the microspheres formed, are preferably selected. Moreover, an excessively high temperature would require an excessively high drop height for the microspheres in order to achieve complete solidification, with the risk of causing the active principle to degrade.
- On taking into consideration this recommended melting temperature range, the excipients in question can be selected from:
- saturated or unsaturated fatty acid glycerides, in particular glycerides containing up to 80 carbon atoms, such as, for example, glyceryl tribehenate, glyceryl palmitate/stearate, glyceryl monostearate, glyceryl monooleate or caprylic/capric glycerides, such as glyceryl tricaprylate/caprate
- saturated polyglycolysed glycerides, such as mixtures of glycerol monoesters, diesters and triesters and of polyethylene glycol mono- and diesters
- hydrogenated oils, such as hydrogenated castor oil
- a wax, such as natural beeswax or synthetic beeswax.
- By way of example, matrix excipients capable of forming microspheres according to the invention can be selected from:
- glyceryl tribehenate, such as sold under the trademark Compritol® 888
- glyceryl palmitate/stearate, such as sold under the trademark Precirol® ATO5
- a hydrogenated castor oil, such as sold under the trademark Cutina® HR
- glyceryl monostearate, such as sold under the trademark Monomuls® 90/25
- glyceryl monooleate, such as sold under the trademark Myverol® 18/99
- glyceryl tricaprylate/caprate, such as sold under the trademark Labrafac® lipophile
- saturated polyglycolysed glycerides, such as sold under the trademarks Gelucire® 50-02 or Labrafil® 2130CS
- a natural beeswax or a synthetic beeswax, such as sold under the trademark Cutina® BW
- a paraffin.
- The excipients used in the context of the invention will furthermore be selected while taking into account the hydrophilic, lipophilic (or hydrophobic) or amphiphilic nature which they may possess and according to the kinetics desired for the release of the active principle.
- In particular, and in a non-limiting way, mixtures of excipients of the type: either glyceryl tribehenate (Compritol® 888)/surfactant (Labrafil® 2130CS) or glyceryl tribehenate (Compritol® 888)/glyceryl monooleate (Myverol® 18/99) or synthetic beeswax (Cutina® BW)/hydrogenated castor oil (Cutina® HR)/glyceryl monostearate (Monomuls® 90/25) have proved to be suitable for fairly immediate release of the active principle.
- By way of example, in vitro dissolution tests were carried out at pH=6.8 for 6 hours according to the method described in the monograph “Dissolution tests for solid oral forms” of the European Pharmacopoeia II in the part General Directions V. 5.4, pp. 1-9 (1995).
- Microspheres comprising from 55% to 60% by weight of product Compritol® 888 or of product Precirol® ATO5, from 30% to 35% by weight of active principle (valproic acid/sodium valproate) and from 10% to 15% by weight of surfactant Labrafil® 2130CS were used for this purpose.
- After 1 hour, 100% of dissolved active principle was recorded in the case of the formulation including the product Precirol® ATO5 and 85%, was recorded for that comprising the product Compritol® 888.
- Likewise, dissolution tests carried out under the same conditions with microspheres containing from 20% to 25% by weight of product Cutina® HR, 20% to 25% by weight of product Cutina® BW, 20% to 25% by weight of product Monumuls® 90/25 and 30% to 35% by weight of active principle (valproic acid/sodium valproate) showed 100% dissolution of the active principle after 1 hour.
- Moreover, an analogous test carried out with 55% to 60% by weight of
product Compritol® 888, 30% to 35% by weight of active principle (valproic acid/sodium valproate) and 10% by weight of product Myverol® 18/99 also revealed an immediate release profile. - Following these tests, it could be concluded that none of the formulations tested and exemplified above exhibits a profile of delayed release of the active principle over a period of 6 hours.
- In contrast, other microsphere formulations involving the product Compritol® 888 as sole matrix excipient have proved to be fairly suitable for delayed release of the active principle.
- The addition of certain hydrophobic substances, such as hydrogenated castor oil (Cutina® HR), beeswax, paraffin, the product Gelucire® 50-02 or the product Labrafac® lipophile, has furthermore made it possible to accentuate the delayed release of the active principle.
- By way of example, microspheres containing from 65 to 70% by weight of the product Compritol® 888 and from 30% to 35% by weight of active principle (valproic acid/sodium valproate) have revealed, during dissolution tests, a slow dissolution profile. Analogous results were recorded from microspheres comprising from 55% to 60% by weight of the
product Compritol® 888, 10% to 15% by weight of the product Cutina® HR, beeswax, paraffin, the product Gelucire® 50-02 or the product Labrafac® lipophile and 30% to 35 by weight of active principle. - In particular, microspheres with the following formulations were subjected to dissolution tests at pH=6.8 for 9 hours according to the method of the European Pharmacopoeia II described above, namely:
% by weight Compritol ® 888 58.37 Adjuvants 10 Valproic acid 9.63 Sodium valproate 22 100.00 - the adjuvants corresponding to the products Cutina® HR, Cutina® BW, paraffin, Gelucire® 50-02 and Labrafac® lipophile.
- The dissolution profiles obtained are reproduced in the appended Figure I, in which figure:
- a) the curve denoted “formula 1” represents the percentages of dissolution of the valproate anion as a function of the time from the above microspheres, in which microspheres the adjuvant is the product Cutina® HR
- b) the curve denoted “
formula 2” represents analogous percentages to the curve “formula 1”, the adjuvant being the product Cutina® BW - c) the curve denoted “formula 3” represents analogous percentages to the curve “formula 1”, the adjuvant being paraffin
- d) the curve denoted “formula 4” represents analogous percentages to the curve “formula 1”, the adjuvant being the product Gelucire® 50-02
- e) the curve denoted “
formula 5” represents analogous percentages to the curve “formula 1”, the adjuvant being the product Labrafac® lipophile. - The results obtained show delayed-release kinetics for the active principle. It can be deduced therefrom that the formulations containing paraffin, hydrogenated castor oil (Cutina® HR) and synthetic beeswax (Cutina® BW) appear as the most advantageous.
- As the active principle used in the present invention is composed of a hydrophobic component, namely valproic acid, and of a hydrophilic component, that is to say a pharmaceutically acceptable salt of this acid, it seems that the most suitable matrix excipients should be amphiphilic substances, in order, by their hydrophobic part, to provide for the delayed release of the active principle and, by their hydrophilic part, to provide for the regulation of the rate of release of this active principle from the excipient.
- It has been found, unexpectedly, that a matrix excipient formed solely of natural beeswax, a typically hydrophobic fatty substance, makes possible a release profile of the active principle which is entirely compatible with a retard pharmaceutical formulation. In addition, this profile proved to be fairly similar to the release profile recorded with known tablets containing a valproic acid/sodium valproate mixture as active ingredient.
- In particular, dissolution tests and pharmacokinetic tests were carried out from:
- either microspheres formed of 68.37 g of natural beeswax as matrix vehicle and of 31.63 g of active principle, namely 9.63 g of valproic acid and 22 g of sodium valproate, hereinafter denoted “Composition A microspheres”.
- The active principle consequently corresponds to a 30.45%/69.55% by weight valproic acid/sodium valproate mixture.
- or a divisible retard tablet formulated with 478 mg of a valproic acid/sodium valproate mixture, namely 145 mg of acid and 333 mg of salt, this tablet comprising in particular methacrylic acid polymers as excipient.
- The active ingredients of this commercial tablet-consequently correspond to a 30.33%/69.67% by weight valproic acid/sodium valproate mixture or to 500 mg of active ingredient expressed as sodium valproate.
- I.—Dissolution Tests
- These tests were carried out in vitro at pH=6.8 according to the method cited above.
- The dissolution profiles obtained are reproduced in the appended Figure II, in which figure
- a) the curve denoted “microspheres” represents the percentages of dissolution of the valproate anion as a function of the time from the above Composition A microspheres
- b) the curve denoted “tablet” represents the percentages of dissolution of the valproate anion as a function of the time from the above divisible retard tablet.
- The results obtained clearly show that the dissolution profile of the Composition A microspheres is close to and resembles the dissolution profile of the tablet, since a difference of only 10% separates them after the first hour, a difference which remains constant for at least 5 hours.
- II.—Pharmacokinetic Tests
- Tests were carried out on three series of 24 healthy subjects, to whom were administered:
- Composition A microspheres in water
- Composition A microspheres in yoghurt
- a divisible retard tablet such as above so that each subject receives a dose of active ingredient (valproic acid/sodium valproate) equivalent to 500 mg expressed as sodium valproate.
- The blood concentration of valproate anion and in particular the maximum blood concentration (Cmax), the time after administration at which this maximum concentration occurs (Tmax) and the residual blood concentration 24 hours after administration were then recorded every hour, from administration, for each subject.
- The results obtained are reproduced in the appended Figure III, in which figure:
- a) the curve denoted “Composition A/water” represents the mean blood concentration obtained with the Composition A microspheres in water
- b) the curve denoted “Composition A/yoghurt” represents the mean blood concentration obtained with the Composition A microspheres in yoghurt
- c) the curve denoted “tablet” represents the mean blood concentration obtained with the divisible retard tablet.
- These results show that the Cmax of the Composition A microspheres is slightly greater than that of the divisible retard tablet, i.e. approximately 16% for the microspheres in water and approximately 22% for the microspheres in yoghurt, whereas the Tmax values prove to be slightly shorter for the microspheres with respect to the tablet.
- Finally, the results of the analyses of variance show that there is no significant difference between the areas under the curves (AUC).
- In other words, these tests enable it to be concluded that there exists no significant difference in bioavailability between the Composition A microspheres and the divisible retard tablet.
- Consequently, microspheres containing from 30% to 35% of active principle in combination with a matrix vehicle entirely composed of beeswax represent microspheres of vital importance.
- Likewise, microspheres of this type, in which the active principle is formed of 25% to 35% of valproic acid and of 65% to 75% of a pharmaceutically acceptable salt of this acid, such as sodium valproate, are particularly preferred for the purposes of the invention.
- Unlike other technologies for the production of spheroids, prilling makes it possible to obtain a so-called monodisperse particle size distribution with the advantage of producing spheres which are regular in size. Consequently, during the administration of the medicament containing them, the amount of such microspheres received by the patient will be constant.
- The pharmaceutical microspheres of the invention possess this advantage, in that they exhibit such a regular spherical shape, with a diameter of between 250 μm and 500 μm, generally of the order of 400 μm.
- If necessary, these microspheres can be covered with a film-forming agent, so as to form, for example, a gastroresistant film.
- In addition, they can be packaged in various pharmaceutical forms, unitary or otherwise, suitable for oral administration. Such pharmaceutical forms can be, for example, a tablet, including a divisible tablet, a capsule, including a hard gelatin capsule, or a powder packaged, for example, in a chartula or in a system for dispensing unit doses, in particular a dispensing/measuring bottle or a container furnished with an adjustable-volume measuring spoon, for example for adjusting doses to the weight of the patient.
- When they are put into pharmaceutical form, the microspheres in question can receive agents which facilitate flow, as well as lubricants, inorganic fillers, such as silicas, talc or aluminium oxide, or alternatively sweeteners, such as aspartame.
- These pharmaceutical forms can advantageously comprise, per administration unit, from 50 to 500 mg of active principle in the form of microspheres according to the invention, in particular from 50 to 250 mg.
- The following non-limiting Examples illustrate the invention:
- Microspheres with the following composition are prepared:
% by weight White beeswax 68.424 Valproic acid 9.576 Sodium valproate 22 100.00 - the preparation being carried out in the following way.
- 68.424 g of white beeswax are introduced into the jacketed vessel of a melting device thermostatically adjusted to 95° C. and then the wax is melted at a temperature of 90° C. to 93° C. while monitoring that the product has completely melted.
- 9.576 g of valproic acid and then 22.000 g of sodium valproate are then dispersed, with slow stirring, in the molten wax maintained at 90° C. and it is confirmed that the two ingredients have dissolved when the mixture becomes clear (no appearance of crystals).
- The mixture is then prilled, at a temperature of 90° C., through 200 μm injectors maintained at a temperature of 87° C. to 91° C. and under a pressure of 0.5 bar. The frequency of the vibrator of the device (5.75×103 to 6.70×103 Hz) is adjusted, so as to individualize the droplets formed, under stroboscopic monitoring at a frequency of 25,000 Hz.
- Microspheres solidified by cooling during their fall in air (drop height: approximately 2.5 m) refrigerated by a countercurrent of cold air or by a liquid nitrogen bath are thus collected at the base of the device. These microspheres have a mean diameter of 400 μm.
- Microspheres were prepared in the same way, but by using other matrix excipients, from the following formulations, which all proved to be clear after dissolution of the active principle (rig appearance Of crystals):
-
% by weight Cutina ® HR 34.185 Cutina ® BW 34.185 Valproic acid 9.63 Sodium valproate 22 100.00 -
% by weight Cutina ® HR 29.185 Cutina ® BW 29.185 Monomuls ® 90-25 10 Valproic acid 9.63 Sodium valproate 22 100.00 -
% by weight Compritol ® 888 58.37 Labrafil ® 2130 CS 10 Valproic acid 9.63 Sodium valproate 22 100.00 -
% by weight Precirol ® ATO 558.37 Labrafil ® 2130 CS 10 Valproic acid 9.63 Sodium valproate 22 100.00 -
% by weight Cutina ® HR 24.185 Cutina ® BW 24.185 Monomuls ® 90-25 20 Valproic acid 9.63 Sodium valproate 22 100.00 -
% by weight Compritol ® 888 68.37 Valproic acid 9.63 Sodium valproate 22 100.00 -
% by weight Compritol ® 888 58.37 Cutina ® HR 10 Valproic acid 9.63 Sodium valproate 22 100.00 -
% by weight Compritol ® 888 58.37 Beeswax 10 Valproic acid 9.63 Sodium valproate 22 100.00 -
% by weight Compritol ® 888 58.37 Paraffin 1.0 Valproic acid 9.63 Sodium valproate 22 100.00 -
% by weight Compritol ® 888 58.37 Gelucire ® 50-02 10 Valproic acid 9.63 Sodium valproate 22 100.00 -
% by weight Compritol ® 888 58.37 Labrafac ® lipophile 10 Valproic acid 9.63 Sodium valproate 22 100.00 -
% by weight Compritol ® 888 58.37 Myverol ® 18/99 10 Valproic acid 9.63 Sodium valproate 22 100.00 -
% by weight Compritol ® 888 34.185 Beeswax 34.185 Valproic acid 9.63 Sodium valproate 22 100.00 - 1) Chartula
- 756.7 mg of microspheres as prepared in Example 1 are introduced into a chartula, so as to form an oral administration unit containing 238.96 mg of active principle composed of 30.4%/69.6% by weight valproic acid/sodium valproate, which corresponds to 250 mg of active principle expressed as sodium valproate.
- 2) Dispenser/Measuring Bottle
- 24 g of microspheres prepared in Example 1, i.e. 8 g of active principle per packaged unit, are introduced into a bottle with a working volume of approximately 45 ml which allows unit doses to be dispensed.
- This bottle makes it possible to dispense approximately 50 unit doses containing 150 mg of active principle composed of 30.4%/69.6% by weight valproic acid/sodium valproate.
Claims (22)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/270,159 US20030157177A1 (en) | 1996-10-07 | 2002-10-15 | Pharmaceutical microspheres containing valproic acid for oral administration |
US11/357,426 US8535721B2 (en) | 1996-10-07 | 2006-02-21 | Pharmaceutical microspheres containing valproic acid for oral administration |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9612201A FR2754177B1 (en) | 1996-10-07 | 1996-10-07 | PHARMACEUTICAL MICROSPHERES OF VALPROIC ACID FOR ORAL ADMINISTRATION |
FR96/12201 | 1996-10-07 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR1997/001762 A-371-Of-International WO1998015268A1 (en) | 1996-10-07 | 1997-10-03 | Pharmaceutical microspheres of valproic acid for oral administration |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/270,159 Continuation US20030157177A1 (en) | 1996-10-07 | 2002-10-15 | Pharmaceutical microspheres containing valproic acid for oral administration |
Publications (1)
Publication Number | Publication Date |
---|---|
US20020001598A1 true US20020001598A1 (en) | 2002-01-03 |
Family
ID=9496427
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/147,788 Abandoned US20020001598A1 (en) | 1996-10-07 | 1997-10-03 | Pharmaceutical microspheres containing valproic acid for oral administration |
US10/270,159 Abandoned US20030157177A1 (en) | 1996-10-07 | 2002-10-15 | Pharmaceutical microspheres containing valproic acid for oral administration |
US11/357,426 Expired - Fee Related US8535721B2 (en) | 1996-10-07 | 2006-02-21 | Pharmaceutical microspheres containing valproic acid for oral administration |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/270,159 Abandoned US20030157177A1 (en) | 1996-10-07 | 2002-10-15 | Pharmaceutical microspheres containing valproic acid for oral administration |
US11/357,426 Expired - Fee Related US8535721B2 (en) | 1996-10-07 | 2006-02-21 | Pharmaceutical microspheres containing valproic acid for oral administration |
Country Status (40)
Country | Link |
---|---|
US (3) | US20020001598A1 (en) |
EP (1) | EP0956010B1 (en) |
JP (1) | JP3523270B2 (en) |
KR (1) | KR100334687B1 (en) |
CN (1) | CN100367945C (en) |
AR (1) | AR013613A1 (en) |
AT (1) | ATE216228T1 (en) |
AU (1) | AU731235B2 (en) |
BR (1) | BR9712268A (en) |
CA (1) | CA2267096C (en) |
CO (1) | CO4900080A1 (en) |
CZ (1) | CZ288876B6 (en) |
DE (1) | DE69712100T2 (en) |
DK (1) | DK0956010T3 (en) |
DZ (1) | DZ2316A1 (en) |
EE (1) | EE03744B1 (en) |
EG (1) | EG24070A (en) |
ES (1) | ES2174293T3 (en) |
FR (1) | FR2754177B1 (en) |
HK (1) | HK1021939A1 (en) |
HR (1) | HRP970537B1 (en) |
HU (1) | HU225103B1 (en) |
ID (1) | ID24596A (en) |
IL (1) | IL128745A (en) |
IS (1) | IS1985B (en) |
ME (1) | ME00664B (en) |
MY (1) | MY120521A (en) |
NO (1) | NO325723B1 (en) |
NZ (1) | NZ334399A (en) |
PL (1) | PL190105B1 (en) |
PT (1) | PT956010E (en) |
RS (1) | RS49602B (en) |
RU (1) | RU2177315C2 (en) |
SI (1) | SI0956010T1 (en) |
SK (1) | SK282113B6 (en) |
TR (1) | TR199900789T2 (en) |
TW (1) | TW508251B (en) |
UY (1) | UY24738A1 (en) |
WO (1) | WO1998015268A1 (en) |
ZA (1) | ZA978954B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060252830A1 (en) * | 2005-05-06 | 2006-11-09 | Brandon Stephen F | Method for the treatment of magnesium and potassium deficiencies |
US20060252831A1 (en) * | 2005-05-06 | 2006-11-09 | Christopher Offen | Method for the treatment of magnesium and potassium deficiencies |
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DE60021570T2 (en) | 1999-06-07 | 2006-05-24 | Altana Pharma Ag | NEW PREPARATION AND PHARMACEUTICAL FORM CONTAINS AN ACID ELASTILE PROTON PUMP INHIBITOR |
WO2004054957A2 (en) * | 2002-12-16 | 2004-07-01 | The University Of British Columbia | Valproic acid analogues and pharmaceutical compositions thereof |
TWI356036B (en) * | 2004-06-09 | 2012-01-11 | Smithkline Beecham Corp | Apparatus and method for pharmaceutical production |
KR20070100686A (en) * | 2004-09-07 | 2007-10-11 | 오르펀 메디칼, 인크. | Improved ghb compositions |
US9149433B2 (en) * | 2004-11-30 | 2015-10-06 | Basf Corporation | Method for formation of micro-prilled polymers |
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CN101543631B (en) * | 2008-03-28 | 2012-01-11 | 沈阳兴齐制药有限公司 | Microspherical substrate containing beeswax, pharmaceutical composition containing microspherical substrate and application thereof |
KR101330889B1 (en) * | 2009-05-12 | 2013-11-18 | (주)아모레퍼시픽 | Composition for prevention of losing hair or promotion of growing hair |
AU2014350208B2 (en) * | 2013-11-13 | 2017-09-07 | Tillotts Pharma Ag | Multi-particulate drug delivery system |
CN104013596A (en) * | 2014-05-16 | 2014-09-03 | 安士制药(中山)有限公司 | Valproic acid softgel and preparation method thereof |
CN105456217A (en) * | 2014-08-27 | 2016-04-06 | 捷思英达医药技术(上海)有限公司 | Divalproex sodium sustained-release agent composition and preparation method thereof |
EP3675268A4 (en) | 2017-08-24 | 2021-05-19 | Mitsui Chemicals, Inc. | Lithium secondary battery and nonaqueous electrolyte solution |
CN110998957B (en) | 2017-08-24 | 2023-03-24 | 三井化学株式会社 | Nonaqueous electrolyte for battery and lithium secondary battery |
FR3087445B1 (en) * | 2018-10-19 | 2021-12-17 | Soc Dexploitation De Produits Pour Les Industries Chimiques Seppic | LIPIDIC COMPOSITION FOR THE ENCAPSULATION OF AN ACTIVE SUBSTANCE AND ALLOWING THE CONTROL OF THE RATE OF RELEASE OF THE SAID ACTIVE SUBSTANCE |
CN111012753A (en) * | 2020-01-07 | 2020-04-17 | 仁和堂药业有限公司 | Method for improving stability of sodium valproate tablets |
CN112274499A (en) * | 2020-11-16 | 2021-01-29 | 仁和堂药业有限公司 | Method for improving stability of sodium valproate tablets |
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DK150008C (en) * | 1981-11-20 | 1987-05-25 | Benzon As Alfred | PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL ORAL POLYDEPOT PREPARATION |
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JP2893191B2 (en) * | 1988-11-08 | 1999-05-17 | 武田薬品工業株式会社 | Controlled release matrix agent |
EP0418596A3 (en) * | 1989-09-21 | 1991-10-23 | American Cyanamid Company | Controlled release pharmaceutical compositions from spherical granules in tabletted oral dosage unit form |
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US6248363B1 (en) * | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
UA80393C2 (en) * | 2000-12-07 | 2007-09-25 | Алтана Фарма Аг | Pharmaceutical preparation comprising an pde inhibitor dispersed on a matrix |
-
1996
- 1996-10-07 FR FR9612201A patent/FR2754177B1/en not_active Expired - Fee Related
-
1997
- 1997-09-24 DZ DZ970166A patent/DZ2316A1/en active
- 1997-10-03 DK DK97943943T patent/DK0956010T3/en active
- 1997-10-03 BR BR9712268-8A patent/BR9712268A/en not_active IP Right Cessation
- 1997-10-03 AU AU45602/97A patent/AU731235B2/en not_active Expired
- 1997-10-03 RU RU99109087/14A patent/RU2177315C2/en active
- 1997-10-03 WO PCT/FR1997/001762 patent/WO1998015268A1/en active IP Right Grant
- 1997-10-03 CO CO97057983A patent/CO4900080A1/en unknown
- 1997-10-03 DE DE69712100T patent/DE69712100T2/en not_active Expired - Lifetime
- 1997-10-03 NZ NZ334399A patent/NZ334399A/en not_active IP Right Cessation
- 1997-10-03 SK SK364-99A patent/SK282113B6/en not_active IP Right Cessation
- 1997-10-03 JP JP51724598A patent/JP3523270B2/en not_active Expired - Lifetime
- 1997-10-03 IL IL12874597A patent/IL128745A/en not_active IP Right Cessation
- 1997-10-03 AT AT97943943T patent/ATE216228T1/en active
- 1997-10-03 CA CA002267096A patent/CA2267096C/en not_active Expired - Lifetime
- 1997-10-03 PT PT97943943T patent/PT956010E/en unknown
- 1997-10-03 RS YUP-178/99A patent/RS49602B/en unknown
- 1997-10-03 ME MEP-1999-178A patent/ME00664B/en unknown
- 1997-10-03 EP EP97943943A patent/EP0956010B1/en not_active Expired - Lifetime
- 1997-10-03 SI SI9730352T patent/SI0956010T1/en unknown
- 1997-10-03 EE EEP199900140A patent/EE03744B1/en unknown
- 1997-10-03 HU HU9903855A patent/HU225103B1/en unknown
- 1997-10-03 ES ES97943943T patent/ES2174293T3/en not_active Expired - Lifetime
- 1997-10-03 ID IDW990095D patent/ID24596A/en unknown
- 1997-10-03 TR TR1999/00789T patent/TR199900789T2/en unknown
- 1997-10-03 CZ CZ19991211A patent/CZ288876B6/en not_active IP Right Cessation
- 1997-10-03 US US09/147,788 patent/US20020001598A1/en not_active Abandoned
- 1997-10-03 CN CNB971985375A patent/CN100367945C/en not_active Expired - Lifetime
- 1997-10-03 PL PL97332249A patent/PL190105B1/en unknown
- 1997-10-03 KR KR1019997002824A patent/KR100334687B1/en not_active IP Right Cessation
- 1997-10-06 AR ARP970104595A patent/AR013613A1/en active IP Right Grant
- 1997-10-06 UY UY24738A patent/UY24738A1/en not_active Application Discontinuation
- 1997-10-07 MY MYPI97004682A patent/MY120521A/en unknown
- 1997-10-07 HR HR970537A patent/HRP970537B1/en not_active IP Right Cessation
- 1997-10-07 EG EG103597A patent/EG24070A/en active
- 1997-10-07 ZA ZA978954A patent/ZA978954B/en unknown
- 1997-11-25 TW TW086117675A patent/TW508251B/en active
-
1999
- 1999-03-11 IS IS4996A patent/IS1985B/en unknown
- 1999-04-06 NO NO19991613A patent/NO325723B1/en not_active IP Right Cessation
-
2000
- 2000-02-15 HK HK00100894A patent/HK1021939A1/en not_active IP Right Cessation
-
2002
- 2002-10-15 US US10/270,159 patent/US20030157177A1/en not_active Abandoned
-
2006
- 2006-02-21 US US11/357,426 patent/US8535721B2/en not_active Expired - Fee Related
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060252830A1 (en) * | 2005-05-06 | 2006-11-09 | Brandon Stephen F | Method for the treatment of magnesium and potassium deficiencies |
US20060252831A1 (en) * | 2005-05-06 | 2006-11-09 | Christopher Offen | Method for the treatment of magnesium and potassium deficiencies |
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