WO2007114797A1 - Porous tablets for subsequent filling with active pharmaceutical ingredient - Google Patents
Porous tablets for subsequent filling with active pharmaceutical ingredient Download PDFInfo
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- WO2007114797A1 WO2007114797A1 PCT/SI2007/000013 SI2007000013W WO2007114797A1 WO 2007114797 A1 WO2007114797 A1 WO 2007114797A1 SI 2007000013 W SI2007000013 W SI 2007000013W WO 2007114797 A1 WO2007114797 A1 WO 2007114797A1
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- Prior art keywords
- active pharmaceutical
- pharmaceutical ingredient
- tablet
- acetate
- solution
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Classifications
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- the objects of the invention are porous tablets for subsequent filling with active pharmaceutical ingredient.
- Tablets according to the invention are made with direct tabletting using excipients that enable subsequent filling of thereof with organic solution of active pharmaceutical ingredient.
- active pharmaceutical ingredient has to be incorporated into appropriate therapeutical system or medicine.
- tablet bases consist only of excipients used in pharmacy, active pharmaceutical ingredient is added subsequently as organic solvent solution.
- Tablets one of the most often used pharmaceutical solid dosage forms are preparations that consist of s single dose of one or more active ingredients. Usually are made in a way that a uniform volume of particles is compressed into a tablet.
- solvents are: acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimetoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4- dioxane, 2-etoyethanol, ethyleneglycol, formamide, hexane, methanol, 2-methohyethanol, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, tetrahydrofuran, toluenea and xylene.
- Class 3 solvents have low toxic potential.
- Amount of of daily consumption of these solvents are 50 mg or more with lower risk to human health.
- These solvents are: heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3 -methyl -1-butanol, methylethylketone, methylisobutylketone, 2-methyl-l-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, acetic acid, acetone, anisole, 1-butabol, 2-butanol, buthyl acetate, tert- butylmethyl ether, cumene, dimethyl sulphoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate and formic acid.
- Formulation contains beside active pharmaceutical ingredient also many different excipients that must be homogenously mixed, which is often difficult task. Compatibility of every excipient with the active pharmaceutical ingredient must be studied. Active pharmaceutical ingredient can adsorb onto equipment surfaces during the production process that can influence the content uniformity and decrease its amount in the tablets. Beside fillers, lubricants are added for improvement of flow properties, antiadhesives for prevention of adhesion onto dye and number of tablet components is rapidly increased. Water with high boiling enthalpy and heat capacity is used for granulation.
- excipinets microcristalline cellulose treated with SiO 2
- These excipients are multifunctional which means that they don't possess only one function as lubricants, glidants, antiadhesives, binders or dissintegrants.
- One component possess two or more properties that enable direct tabletting by use of lower number of excipients.
- High functionality excipients have good flow properties and good compressibility. However, it is in any case not possible to avoid dusting, especially with active pharmaceutical ingredient and to ensure drag content uniformity at low dosage tablets wich is in correlation with problems for ensuring homogenous tabletting mass. Nonhomogenous distribution of lubricant can decrease drag dissolution rate and influence compressibility of tabletting mass.
- Nonhomogenous active pharmaceutical ingredient distribution in granulate can be influenced by nonhomogenous distribution of a binder during granulation. Beside that, both procedures demand cleaning of equipment, because it has to be proven that traces of active pharmaceutical ingredient that could contaminate next batch of a product containing new active pharmaceutical ingredient, have been removed. It is necessary to find an appropriate excipients for every active pharmaceutical ingredient separately for tabletting which is of great pretension and retardatory.
- drag can be sprayed in the form of solution or suspension onto the appropriate carrier or with absorption of drag solution into porous carrier particles (for example porous silicone dioxide) and drying which increase production costs. After the drying, for improvement of flow properties and compressibility excipients should be added to particles loaded with the drag, and homogenous distribution of the active pharmaceutical ingredient in the tabletting mass should be ensured.
- porous carrier particles for example porous silicone dioxide
- Invention task is to reduce or dispatch problems related to known procedures of tablet production.
- porous tablets for subsequent filling with active pharmaceutical ingredient where fore prepared porous tablets are filled with organic solvent solution and subsequent dried.
- Figure 3 Content of ketoprofen in tablet after one and multiple fillings from ethanol solution.
- Bases of porous tablets according to the invention do not contain active pharmaceutical ingredient and consist only of excipients used in pharmacy that are not soluble in organic solvents and do not disintegrate in contact with these solvents.
- excipients are lactose, SiO 2 and with SiO 2 treated microcrystalline cellulose (commercial name PROSOLV HD 90).
- Tablets without active pharmaceutical ingredient according to the invention are made with direct tabletting of lactose, SiO 2 or with SiO 2 treated microcrystalline cellulose or any combination of these excipients and are meant for filling by use of organic solvent or combination of solvents in which active pharmaceutical ingredient dissolve.
- solventcs can be heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3 -methyl -1-butanol, methylethylketone, methylisobutylketone, 2-methyl-l-propanol, pentane, 1/pentanol, 1- propanol, 2-propanol, propyl acetate, acetic acid, acetone, anisole, 1-butanol, 2-butanol, buthyl acetate, tert-butylmethyl ether, cumene, dimethyl sulphoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, acetonitrile, chlorobenzene, chloroform, cyclohexane 1,2- dichloroethene, dichloromethane, 1,2-dimetoxyethane, N,N-dimethylacet
- Invention comprehend two procedures of filling. Bases of tablets can be immersed in a surplus of organic solution of active pharmaceutical ingredient. Every tablet from the same batch due to capillary effect absorbs same mass of the solution. According to second procedure active pharmaceutical ingredient solution is added separately into every tablet with appropriate dosing device, for example pipette in the way where whole solution amount added is absorbed into the tablet. Both examples enable reproducible and accurate dosing of active pharmaceutical ingredient into each tablet. Drying until removal of a solvent from the tablet follows to the limit permitted by regulations of official Pharmacopoeia. Active pharmaceutical ingredient has to be soluble in the organic solvent or in solvent mixture to the extent that enable by one, two, three or multiple filling procedure of the same tablet, assurance of therapeutical dose content.
- Tablets according to the invention can be of any colour, texture or shape, for example round, oval, biconcave, rectangular, square, polygonal etc. Tablet mass can vary from 50 mg to 1000 mg preferentially from 50 mg to 500 mg.
- Tablets are prepared with direct tabletting of microcrystalline cellulose treated with SiO 2 with diameter of 12 mm and mass of 440 mg. After immersion of tablets in organic solvent for several minutes disintegration or retention of their shape is checked.
- Tablets are prepared with direct tabletting of lactose monohydrate /SiO 2 / microcrystalline cellulose treated with SiO 2 in proportion 30/20/50 with diameter of 10 mm and mass of 440 mg. After immersion of tablets in organic solvent for several minutes disintegration or retention of their shape is checked.
- Tablets are prepared by direct tabletting of microcrystalline cellulose treated with SiO 2 with diameter of 10 mm and mass of 440 mg. Tablets are filled by immersion in solution of ketoprofen in ethyl acetate (20 % weight/volume concentration) for one minute and drying
- Ketoprofen content in the tablet is determined spectrophotometrically by dissolving in ethanol and concentration determination at wavelength of257 nm.
- ketoprofen (g) mass in the tablet (g) mass in the tablet (g)
- Tablets are made with direct tabletting of silicified microcrystalline cellulose (PROSOLV ® -HD90) with diameter of 10 mm, mass of 240 and 455 mg filled with diclofenac in the way that from the both sides of the tablet 75 microliter of tetrahydrofurane solution (20% weight/volume concentration) of diclofenac is added with a pipette.
- Diclofenac content in the tablet is determined by dissolution in methanol and spectrophotometical determination of concentration at wavelength of 282 nm.
- Tablets according to the invention enable faster and cheaper development of formulation for production of drugs in comparison to conventional tablet production methods. Les equipment and components for tablet production is needed. There is no dusting and equiplent contamination of equipment that is used for granulation and tabletting eith active pharmaceutical ingredient, cleaning of equipment is less demanding in comparison to conventional methods of tablet production where traces of active pharmaceutical ingredient have to be removed. In comparison to granulation energy consumption is less because there is no water evaporation that has high heat of evaporation.
Abstract
Bases of porous tablets for subsequent filling with active pharmaceutical ingredient are made with known processes and are composed only of excipients used in pharmacy that are not soluble in organic solvents, in contact with these solvent do not disintegrate, and are then filled by use of organic solvent solution of active pharmaceutical ingredient and then dried. Excipients are lactose and/or SiO2 and/or with SiO2 modified microcrystalline cellulose in different proportions. Organic solvents in which active pharmaceutical ingredient is dissolved are heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl -1-butanol, methylethylketone, methylisobutylketone, 2-methyl-l-propanol, pentane, 1/pentanol, 1- propanol, 2-propanol, propyl acetate, acetic acid, acetone, anisole, 1-butanol, 2-butanol, buthyl acetate, tert-butylmethyl ether, cumene, dimethyl sulphoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, acetonitrile, chlorobenzene, chloroform, cyclohexane 1,2- dichloroethene, dichloromethane, 1,2-dimetoxyethane, N,N-dimethylacetamide, N5N- dimethylformamide, 1,4-dioxane, 2-etoxyethanol, ethyleneglycol, formamide, hexane, methanol, 2-methohyethanol, methylcyclohexane, N-methylpzrrolidone, nitromethane, pyridine, tetrahydrofuran, toluene, xylene or mixtures of two or more of these listed liquids Tablet bases are immersed into surplus of organic solution of active pharmaceutical ingredient. This solution can be added into each tablet separately usindg appropriate dosing device preferentially pipette in the way that tablet absorbs whole amount of solution added.
Description
POROUS TABLETS FOR SUBSEQUENT FILLING WITH ACTIVE PHARMACEUTICAL INGREDIENT
Field of the invention
The objects of the invention are porous tablets for subsequent filling with active pharmaceutical ingredient. Tablets according to the invention are made with direct tabletting using excipients that enable subsequent filling of thereof with organic solution of active pharmaceutical ingredient. For achievement of therapeutical effect active pharmaceutical ingredient has to be incorporated into appropriate therapeutical system or medicine. According to the invention tablet bases consist only of excipients used in pharmacy, active pharmaceutical ingredient is added subsequently as organic solvent solution.
State of the Art
Tablets and tabletting
Tablets, one of the most often used pharmaceutical solid dosage forms are preparations that consist of s single dose of one or more active ingredients. Usually are made in a way that a uniform volume of particles is compressed into a tablet.
Older method for tablet production is granulation. Development of new excipients and modification of old ones enabled also direct tabletting. Substance used for this purpose is spray dried lactose. Other substances are microcrystalline cellulose, starch 1500 (compressible form of starch), dicalcium phosphate and different sugars. Biggest advantage of direct tabletting in comparison to granulation is lower price. For the tablet production less time, equipment and space, less validations and energy is needed. Also disadvantages of direct tabletting exist:
-it is difficult to ensure equal distribution of components and prevent demixing of formulations with low dosage active pharmaceutical ingredients,
-fillers used for direct tabletting are more expensive than fillers used for granulation,
-limitations of production of colorized tablets
-dusting problems
To tablets with high content of active pharmaceutical ingredient only little amount of excipients can be added. These don't contribute enough to properties improvement and disable direct tabletting. Micronization of active pharmaceutical ingredient that is used for improvement of
dissolution rate leads to surface area increase, agglomeration and interaction with excipients increase and this leads to worsening of flow properties and mixture homogeneity. Changeable properties of active pharmaceutical ingredient and excipients can influence reproducibility of tabletting. Costs of testing ingredients for direct tabletting are higher than for ingredients used for granulation. Direct tabletting demands careful chose of excipients, appropriate flow properties, homogenous distribution of components in tabletting mass and knowledge of formulation and production parameters that can influence compressibility and dissolution of active pharmaceutical ingredient out of the tablet.
Filling of porous materials with solution or suspension of active pharmaceutical ingredient
In the field of pharmacy filling of SiO2 particles with active pharmaceutical ingredient is known in the way where surplus of solution or suspension in appropriate solvent (water, acetone, chloroform) is mixed with these particles. After equilibration particles are washed with solvent and dried at normal or reduced pressure. (Otsuka M, Tokumitsu K, Matsuda Y. Solid dosage form preparation from oily medicines and their drug release. Effect of degree of surface modification of silica gel on the drug release from phytonadione-loaded silica gels. J Control Release 2000; 67: 369-384, Chen J, Ding H,, Wang SJ, Park JB. Preparation and characterization of porous hollow silica nanoparticles for drug delivery application. Biomaterials 2004 ; 25: 723-727). Disadvantage of described filling of particles is use of excess of active pharmaceutical ingredient which is lost by washing and the process can be modified by use of minimal amount of solution or suspension for complete absorption and adsorption. Filling procedure with active pharmaceutical ingredient can be repeated several times to improve filling effectiveness and achieve better pore filling. It is possible to achieve content of 500 mg of active pharmaceutical ingredient in 1 g of the carrier (Ohta KM, Fuji M, Takei T, Chikazawa M. Development of a simple method for the preparation of a silica gel based controlled delivery system with a high drug content. Eur J Pharm Sci 2005; 26:87-96). For production of pharmaceutical products different solvents can be used. All ingredients and products must be tested on a solvent content for solvents that are likely to be present after their production. Purpose of solvent content limitation in pharmaceutical products is patient protection. In the drug production use of less toxic solvents and their residuals in the products that are toxicologically acceptable is desired. Residual solvents are defined as volatile organic chemicals that are used or produced in the production of active pharmaceutical ingredients and
excipients. Depending on the medical consequences for the human health they are divided into three groups. Class 1 solvents are carcinogens, strongly suspected human carcinogens and environmental hazards. They should be avoided. Class 2 solvents are not genotoxic, and do not cause irreversible toxicity such as neurotoxicity or teratogenicity. These solvents are suspected of other significant but reversible toxicities. Limit value of each of these solvents is defined. These solvents are: acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimetoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4- dioxane, 2-etoyethanol, ethyleneglycol, formamide, hexane, methanol, 2-methohyethanol, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, tetrahydrofuran, toluenea and xylene. Class 3 solvents have low toxic potential. Amount of of daily consumption of these solvents are 50 mg or more with lower risk to human health. These solvents are: heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3 -methyl -1-butanol, methylethylketone, methylisobutylketone, 2-methyl-l-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, acetic acid, acetone, anisole, 1-butabol, 2-butanol, buthyl acetate, tert- butylmethyl ether, cumene, dimethyl sulphoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate and formic acid.
Technical problem
Production of tablets using conventional procedures direct tabletting and granulation have certain disadvantages. Formulation contains beside active pharmaceutical ingredient also many different excipients that must be homogenously mixed, which is often difficult task. Compatibility of every excipient with the active pharmaceutical ingredient must be studied. Active pharmaceutical ingredient can adsorb onto equipment surfaces during the production process that can influence the content uniformity and decrease its amount in the tablets. Beside fillers, lubricants are added for improvement of flow properties, antiadhesives for prevention of adhesion onto dye and number of tablet components is rapidly increased. Water with high boiling enthalpy and heat capacity is used for granulation.
For a decrease of number of components high functionality excipinets (microcristalline cellulose treated with SiO2) can be used. These excipients are multifunctional which means that they don't possess only one function as lubricants, glidants, antiadhesives, binders or dissintegrants. One component possess two or more properties that enable direct tabletting by use of lower number of excipients. High functionality excipients have good flow properties and
good compressibility. However, it is in any case not possible to avoid dusting, especially with active pharmaceutical ingredient and to ensure drag content uniformity at low dosage tablets wich is in correlation with problems for ensuring homogenous tabletting mass. Nonhomogenous distribution of lubricant can decrease drag dissolution rate and influence compressibility of tabletting mass. Disadvantages of granulation are high energy consumption for solvent evaporation (usually water) during drying of a granulate and additional equipment needed for granulate production. Nonhomogenous active pharmaceutical ingredient distribution in granulate can be influenced by nonhomogenous distribution of a binder during granulation. Beside that, both procedures demand cleaning of equipment, because it has to be proven that traces of active pharmaceutical ingredient that could contaminate next batch of a product containing new active pharmaceutical ingredient, have been removed. It is necessary to find an appropriate excipients for every active pharmaceutical ingredient separately for tabletting which is of great pretension and retardatory.
For ensuring content uniformity of active pharmaceutical ingredient in the formulation drag can be sprayed in the form of solution or suspension onto the appropriate carrier or with absorption of drag solution into porous carrier particles (for example porous silicone dioxide) and drying which increase production costs. After the drying, for improvement of flow properties and compressibility excipients should be added to particles loaded with the drag, and homogenous distribution of the active pharmaceutical ingredient in the tabletting mass should be ensured.
Invention task is to reduce or dispatch problems related to known procedures of tablet production.
According to the invention problem is solved with porous tablets for subsequent filling with active pharmaceutical ingredient where fore prepared porous tablets are filled with organic solvent solution and subsequent dried.
Description of the problem solution with examples
Invention is decribed with added figures and examples.
Figure 1 : Dissolution of ketoprofen powder and ketoprofen from the tablet filled from ethanol solution in chloride buffer with pH=1.0.
Figure 2: Dissolution of ketoprofen powder and ketoprofen from the tablet filled from ethanol solution in phosphate buffer with pH=7.4..
Figure 3: Content of ketoprofen in tablet after one and multiple fillings from ethanol solution.
Bases of porous tablets according to the invention do not contain active pharmaceutical ingredient and consist only of excipients used in pharmacy that are not soluble in organic solvents and do not disintegrate in contact with these solvents. These excipients are lactose, SiO2 and with SiO2 treated microcrystalline cellulose (commercial name PROSOLV HD 90). Tablets without active pharmaceutical ingredient according to the invention are made with direct tabletting of lactose, SiO2 or with SiO2 treated microcrystalline cellulose or any combination of these excipients and are meant for filling by use of organic solvent or combination of solvents in which active pharmaceutical ingredient dissolve. These solventcs can be heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3 -methyl -1-butanol, methylethylketone, methylisobutylketone, 2-methyl-l-propanol, pentane, 1/pentanol, 1- propanol, 2-propanol, propyl acetate, acetic acid, acetone, anisole, 1-butanol, 2-butanol, buthyl acetate, tert-butylmethyl ether, cumene, dimethyl sulphoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, acetonitrile, chlorobenzene, chloroform, cyclohexane 1,2- dichloroethene, dichloromethane, 1,2-dimetoxyethane, N,N-dimethylacetamide, N5N- dimethylformamide, 1,4-dioxane, 2-etoxyethanol, ethyleneglycol, formamide, hexane, methanol, 2-methohyethanol, methylcyclohexane, N-methylpzrrolidone," nitromethane, pyridine, tetrahydrofuran, toluene, Xylene or mixtures of two or more of these listed liquids
Invention comprehend two procedures of filling. Bases of tablets can be immersed in a surplus of organic solution of active pharmaceutical ingredient. Every tablet from the same batch due to capillary effect absorbs same mass of the solution. According to second procedure active pharmaceutical ingredient solution is added separately into every tablet with appropriate dosing device, for example pipette in the way where whole solution amount added is absorbed into the tablet. Both examples enable reproducible and accurate dosing of active pharmaceutical ingredient into each tablet. Drying until removal of a solvent from the tablet follows to the limit permitted by regulations of official Pharmacopoeia. Active pharmaceutical ingredient has to be soluble in the organic solvent or in solvent mixture to the extent that enable by one, two, three or multiple filling procedure of the same tablet, assurance of therapeutical dose content. Produced tablets depending on water buffer solution
composition disintegrate immediately so that dissolution of active pharmaceutical ingredient depends on its properties or disintegrate or dissolve slowly and by this modify dissolution of active pharmaceutical ingredient in a retarded or controlled manner. Tablets according to the invention can be of any colour, texture or shape, for example round, oval, biconcave, rectangular, square, polygonal etc. Tablet mass can vary from 50 mg to 1000 mg preferentially from 50 mg to 500 mg.
EXAMPLE A
Tablets are prepared with direct tabletting of microcrystalline cellulose treated with SiO2 with diameter of 12 mm and mass of 440 mg. After immersion of tablets in organic solvent for several minutes disintegration or retention of their shape is checked.
EXAMPLE B
Tablets are prepared with direct tabletting of lactose monohydrate /SiO2/ microcrystalline cellulose treated with SiO2 in proportion 30/20/50 with diameter of 10 mm and mass of 440 mg. After immersion of tablets in organic solvent for several minutes disintegration or retention of their shape is checked.
EXAMPLE C
Tablets are prepared by direct tabletting of microcrystalline cellulose treated with SiO2 with diameter of 10 mm and mass of 440 mg. Tablets are filled by immersion in solution of ketoprofen in ethyl acetate (20 % weight/volume concentration) for one minute and drying
(pressure 300 mbar, temperature 60 0C). Ketoprofen content in the tablet is determined spectrophotometrically by dissolving in ethanol and concentration determination at wavelength of257 nm.
Empty tabletMass of the tablet andCalculated ketoprofenMeasured ketoprofen mass (g) ketoprofen (g) mass in the tablet (g) mass in the tablet (g)
0,4470 0,4854 0,0384 0,0370 ;
0,4444 0,4832 0,0388 0,0384
0,4441 0,4828 0,0387 0,0402 ■
0,4431 0,4836 0,0405 0,0426
EXAMPLE D
Tablets are made with direct tabletting of silicified microcrystalline cellulose (PROSOLV®-HD90) with diameter of 10 mm, mass of 240 and 455 mg filled with diclofenac in the way that from the both sides of the tablet 75 microliter of tetrahydrofurane solution (20% weight/volume concentration) of diclofenac is added with a pipette. Diclofenac content in the tablet is determined by dissolution in methanol and spectrophotometical determination of concentration at wavelength of 282 nm.
Empty tabletMass of the tablet andCalculated mass ofMeasured mass of mass (g) diclofenac (g) diclofenac in tablet (g) diclofenac in tablet (g)
0,4460 0,4756 0,0296 0,0284
0,4406 0,4696 0,0290 0,0285
0,4417 0,4720 0,0303 0,0294
EXAMPLE E
With direct tabletting 400 mg tablets are made (50% silica gel+50% lactose) and filled with ethanol solution of ketorpofen [7g/15ml[. After drying tablets contain 40 mg of ketorpofen. Dissolution of tablets filled with ketorpofen lasts 24 hours in chloride buffer pH= 1.0 and temperature 37 °C. At the same conditions dissolution of pure ketoprofen powder takes place (40 mg). Concentration of released ketoprofen from the tablet and powder is determined spectrophotometrically at wavelenght of 257 nm. Diagram according to Figure 1 represents dissolution of ketoprofen powder and ketoprofen from the tablet filled from ethanol solution in chloride buffer with pH=l .0.
EXAMPLE F
1
With direct tabletting 400 mg tablets are made (50% silica gel+50% lactose) and filled with ethanole solution of ketorpofen [7g/15ml]. After drying tablets contain 40 mg of ketorpofen. Dissolution of tablets filled with ketorpofen lasts 24 hours in phosphate buffer pH= 7.4 and temperature 37 °C. At the same conditions dissolution of pure ketorpofen powder takes place
(40 mg). Concentration of released ketoprofen from the tablet and powder is determined spectrophotometrically at wavelenght of 257 nm. Diagram according to Figure 2 represents dissolution of ketoprofen powder and ketoprofen from the tablet filled from ethanol solution in chloride buffer with pH=7.4.
EXAMPLE G
With direct tabletting 400 mg tablets are made (50% silica gel+50% lactose). Tablets are filled with ethanole solution of ketorpofen [5g/10ml] by immersion in ethanol solution of ketoprofen, drying and repeated filling by immersion into ethanol solution of active pharmaceutical ingredient. After each filling ketoprofen content in the tablet is determined by dissolution. Diagram according to figure 3 shows ketoprofen content in tablet after one and multiple fillings.
Tablets according to the invention enable faster and cheaper development of formulation for production of drugs in comparison to conventional tablet production methods. Les equipment and components for tablet production is needed. There is no dusting and equiplent contamination of equipment that is used for granulation and tabletting eith active pharmaceutical ingredient, cleaning of equipment is less demanding in comparison to conventional methods of tablet production where traces of active pharmaceutical ingredient have to be removed. In comparison to granulation energy consumption is less because there is no water evaporation that has high heat of evaporation.
Claims
1. Porous tablets for subsequent filling with active pharmaceutical ingredient where are the tablet bases made with known procedures, characterized in that the tablet bases consist only of excipients used in pharmacy that are not soluble in organic solvents and do not disintegrate in contact with these solvents and are then filled by use of organic solution of active pharmaceutical ingredient and subsequently dried.
2. Tablets according to claim 1, characterized in that the excipients are lactose and/or SiO2 and/or with SiO2 modified microcristalline cellulose in different proportions.
3. Tablets according to claim 1, characterized in that the organic solvents used for dissolution of active pharmaceutical ingredient can be heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3 -methyl -1-butanol, methylethylketone, methylisobutylketone, 2-methyl-l-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, acetic acid, acetone, anisole,, 1- butabol, 2-butanol, buthyl acetate, tert-butylmethyl ether, cumene, dimethyl sulphoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, acetonitrile, chlorobenzene, chloroform, cyclohexane 1,2-dichloroethene, dichloromethane, 1,2-dimetoxyethane, N5N- dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-etoxyethanol, ethyleneglycol, formamide, hexane, methanol, 2-methohyethanol, methylcyclohexane, N-methylpzrrolidone, nitromethane, pyridine, tetrahydrofuran, toluene, xylene or mixture of two or more of these solvents.
4. Tablets according to claim 1, characterized in that to the powder mixture lubricant is added before tabletting
5. Tablets according to claim 1, characterized in that the lubricant comprises Mg stearate,
6. Tablets according to claim 1, characterized in that the tablets according to claim 1, wherein tablet mass is between 50 and 1000 mg.
7. Procedure of production of porous tablet for subsequent filling with active pharmaceutical ingredient according to claims 1 to 5, characterized in that the tablet bases immersed into surplus of organic solution of active pharmaceutical ingredient.
8. Procedure of production of porous tablet for subsequent filling with active pharmaceutical ingredient according to claims 1 to 5, characterized in that to the tablet bases solution of active pharmaceutical ingredient is added separately to each tablet using appropriate dosing device preferentially pipette in the way that every tablet absorbs whole amount of the solution.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI200600081A SI22237A (en) | 2006-04-06 | 2006-04-06 | Porous tablets for subsequent filling with medicinal agent |
| SIP-200600081 | 2006-04-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2007114797A1 true WO2007114797A1 (en) | 2007-10-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SI2007/000013 WO2007114797A1 (en) | 2006-04-06 | 2007-03-21 | Porous tablets for subsequent filling with active pharmaceutical ingredient |
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| Country | Link |
|---|---|
| SI (1) | SI22237A (en) |
| WO (1) | WO2007114797A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010028843A1 (en) * | 2008-09-11 | 2010-03-18 | Univerza V Ljubljani | Tablets for subsequent nanoparticle suspension filling using ultrasound |
| RU2483715C2 (en) * | 2010-12-30 | 2013-06-10 | Общество с ограниченной ответственностью "АКАДЕМФАРМ" | Solid dosage form of preparations of memantine and its salts |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5558880A (en) * | 1989-12-22 | 1996-09-24 | Janssen Pharmaceutica Inc. | Pharmaceutical and other dosage forms |
| US6399591B1 (en) * | 2000-01-19 | 2002-06-04 | Yung-Shin Pharmaceutical Ind. Co., Ltd. | Chargeable pharmaceutical tablets |
| WO2006000229A2 (en) * | 2004-06-28 | 2006-01-05 | Lifecycle Pharma A/S | Porous tablets as carriers for liquid formulations |
-
2006
- 2006-04-06 SI SI200600081A patent/SI22237A/en not_active IP Right Cessation
-
2007
- 2007-03-21 WO PCT/SI2007/000013 patent/WO2007114797A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5558880A (en) * | 1989-12-22 | 1996-09-24 | Janssen Pharmaceutica Inc. | Pharmaceutical and other dosage forms |
| US6399591B1 (en) * | 2000-01-19 | 2002-06-04 | Yung-Shin Pharmaceutical Ind. Co., Ltd. | Chargeable pharmaceutical tablets |
| WO2006000229A2 (en) * | 2004-06-28 | 2006-01-05 | Lifecycle Pharma A/S | Porous tablets as carriers for liquid formulations |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010028843A1 (en) * | 2008-09-11 | 2010-03-18 | Univerza V Ljubljani | Tablets for subsequent nanoparticle suspension filling using ultrasound |
| RU2483715C2 (en) * | 2010-12-30 | 2013-06-10 | Общество с ограниченной ответственностью "АКАДЕМФАРМ" | Solid dosage form of preparations of memantine and its salts |
Also Published As
| Publication number | Publication date |
|---|---|
| SI22237A (en) | 2007-10-31 |
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