SI22237A - Porous tablets for subsequent filling with medicinal agent - Google Patents

Abstract

The bases of porous tablets for subsequent filling with medicinal agent are made according to known procedures and consist only of auxiliary substances for pharmaceutical application which are non-soluble in organic solvents and are not disintegrated in contact with them while they are subsequently filled by using solution of the medicinal agent in an organic solvent with subsequent drying. The auxiliary substances are lactose and/or SiO2 and/or SiO2 processed microcrystal cellulose in various proportions. The organic solvents which the pharmaceutical substance is solved in: heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethylketone, methylisobutilketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propylacetate, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, t- butylmethyl aether, cumol, dimethyl sulphoxide, ethanol, ethyl acetate, ethyl aether, ethyl fumarate, formic acid, acetonitrile, chlorobenzene, chloroform,cyclohexane, 1,2-dichlorinethane, dichlormethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N- dimethylformamide, 1,4-dioxane, 2-etoxyethanol, ethylen-glycol, formamide, hexane, methanol, methylbutilketon, methylcyclohexane, N-methylpirolidon, nitromethane, pyridine, tetrahydrofuran, toluen, xylene or mixture of two or more of the aforementioned solvents. The standard tablets are immersed into a saturated solution of the pharmaceutical agent in organic solvent or the solvent is added separately to each tablet with the adequate dosage device, preferably pipette so that the tablet absorbs the complete quantity of the added solution.

Description

Porous postpill tablets

FIELD OF THE INVENTION

The subject of the invention are porous active substance refillable tablets. The tablets of the invention are made by direct tableting of excipients that allow the pharmaceutical tablets to be subsequently filled with a solution of the active ingredient in an organic solvent. In order to achieve a therapeutic effect, the active substance must be incorporated into the appropriate therapeutic system or drug. According to the invention, the base tablets consist only of excipients used in pharmacy, and the active ingredient is subsequently added as a solution in an organic solvent.

The state of the art

Tablets and tableting

One of the most commonly used pharmaceutical forms is tablets, that is, solid pharmaceutical forms containing a single dose of one or more active ingredients. They are usually made in such a way that a uniform volume of particles is compressed into a tablet.

An older method for making tablets is granulating. The development of new excipients and the modification of old ones also enabled direct tableting. The compound used for this purpose is lactose obtained by spray drying. Other compounds include microcrystalline cellulose, starch 1500 (a starchy form of starch), dicalcium phosphate and various sweeteners. The biggest advantage of direct tableting is the lower cost compared to granulating. Making tablets takes less time, equipment and space, less validation and energy consumption. There are also some negative features of direct tableting, in particular:

- it is difficult to ensure a uniform distribution of the components and to prevent the mixing of low-dose formulations,

- fillers used for direct tableting are more expensive than granules,

- restrictions on the production of colored tablets,

- dusting problems.

Tablets with a high content of the active substance may have only a few excipients added which do not sufficiently improve the properties and prevent direct tabletting. Micronizing the substance used to improve the rate of dissolution leads to an increase in surface area

-2 owing to which agglomeration and interactions with auxiliary substances increase, which leads to a deterioration of the flow properties and homogeneity of the mixture. Variable properties of the active substance and of the excipients can significantly affect the reproducibility of the tablet. The cost of testing raw materials for direct tabletting is higher than for granulating raw materials. Direct tableting thus requires careful selection of excipients, appropriate flow properties, homogeneous distribution of components in the tabletting mass, and knowledge of the formulation and manufacturing parameters that can affect the compressibility and dissolution of the active substance from the tablet.

Filling of porous substances with solution or suspension of the active substance

In the field of pharmacy, the filling of SiO ₂ particles with the active ingredient is known to be mixed with excess solution or suspension with a suitable solvent (water, acetone, chloroform). After equilibration, the particles were washed with pure solvent and dried under 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). The downside of such particle filling is the use of excess active substance, which is lost by flushing, so the process can be modified by using the minimum amount of solution or suspension required for complete adsorption and absorption. The process of filling with the active ingredient can be repeated several times, thus increasing the pores in the particles and increasing the efficiency. A content of 500 mg of the active ingredient in 1 g of carrier can be achieved (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).

Different types of solvents can be used for the manufacture of pharmaceutical products, but all substances and products must be tested for the solvent content that is most present in their manufacture. The purpose of limiting the solvent content of pharmaceutical products is to protect the patient. The use of less toxic solvents and residues in products that are toxicologically acceptable are desirable in the manufacture of medicines. Residual solvents are defined as volatile organic compounds used or produced in the manufacture of active substances and excipients. Considering the possible health effects on human health, we divide them into three groups. Class 1 solvents are carcinogenic, very possibly carcinogenic and harmful to the environment. These solvents are avoided.

-3 Class 2 solvents are not genotoxic, causing irreversible toxicities such as neurotoxicity or teratogenicity. These solvents may be toxic to some extent but their toxicity is reversible. Their use is limited. The content limit for each of these solvents in pharmaceuticals is known. These solvents are: acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, dichloromethane, 1,2-dimethoxyethane, N, N-dimethylacetamide, N, N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, methylbutyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, tetrahydrofuran, toluene and xylene. Class 3 solvents have low toxic potential. The limit for determining the daily dose of solvent that a person can ingest daily is 50 mg or more with these solvents, with a very low risk for human health. These solvents are: heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethylketone, methylisobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate , acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, t-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl fumarate and formic acid.

A technical problem

The manufacture of tablets by known methods of direct tabletting and granulation have certain disadvantages. In addition to the active substance, the formulation contains many different excipients that must be mixed homogeneously, which is often very challenging. The compatibility of the active substance with each of the excipients must be examined. The active substances can also be adsorbed on the surfaces of the equipment they come in contact with during the tablet manufacturing process, which can affect the evenness of the contents and reduce the amount of the active substance in the tablets. In addition to the filler, it is used to provide the flow properties of the slide, to prevent adhesion to sealing anti-adhesives, thereby increasing the number of components in the tablet rapidly. Granulation uses water which has a high evaporative heat and heat capacity.

Highly functional excipients (such as SiO ₂ treated microcrystalline cellulose) are typically used to reduce layouts. These excipients are multifunctional, which means that they do not have a single function as sliders, lubricants, antiadhesives, binders or disintegrators. One ingredient has two or more of the following properties, allowing direct tableting using less excipients. Highly functional excipients can have good flow properties and good compressibility. However, tableting problems cannot be avoided, especially with the active ingredient and by providing the uniformity of the content of the active substance in low-dose tablets, which is

-4 related to difficulties in ensuring the homogeneity of tablet masses. The inhomogeneous distribution of the active substance in the tabletting mixture may be the result of inefficient mixing or mixing. Excessive glider addition can reduce the rate of dissolution of the active substance and affect the compressibility of the tabletting mass. When granulating, the disadvantages of the process are the high energy consumption of solvent evaporation (most often water) in the drying of the granulate, and the accessories required to produce the granulate. When granulating, the non-homogeneous distribution of the binder may affect the uneven distribution of the active ingredient in the granulate. In addition, both procedures require the cleaning of the equipment, and it must be demonstrated that the cleaning has removed traces of the active substance that could cause contamination of the next batch of tablet production containing the second active ingredient. For each ingredient, it is necessary to find suitable excipients suitable for its tableting, which is difficult and time consuming.

To ensure uniformity of the active ingredient content of the formulation, the active ingredient can be sprayed in solution or suspension onto a suitable carrier or by absorbing the active ingredient solution into porous carrier particles (for example silica) and drying, which increases the cost of production. After drying, excipients must be added to the active ingredient to improve flow properties and compressibility, to ensure homogeneity of distribution of the active ingredient in the tabletting mixture.

It is an object of the invention to provide a tablet that will reduce or eliminate problems of known tablet manufacturing processes.

According to the invention, the problem is solved with a porous active substance refill tablet wherein the prepared porous pharmaceutical tablet is filled with the active ingredient solution in an organic solvent and the solvent is removed.

Description of a solution to a problem with implementation examples

The invention will be described with the accompanying drawings and embodiments.

Figure 1: Dissolution of ketoprofen and ketoprofen powder from a tablet filled with ethanol solution in chloride buffer with pH = T, 0.

-5Figure 2: Dissolution of a ketoprofen and ketoprofen powder from a tablet filled with ethanol solution in phosphate buffer with pH = 7.4.

Figure 3: Ketoprofen content of the tablet after single and multiple refills of ethanol solution.

The basics of the pharmaceutical tablets of the invention do not contain the active substance and are composed of excipients used in pharmacy that are insoluble in organic solvents and do not decompose in contact with them. These substances are lactose, SiO _2, and microcrystalline cellulose treated with SiO ₂ (the special name is PROSOLV HD 90). The active substance tablets of the invention are made by direct tabletting of lactose, SiO ₂ or SiO ₂ treated microcrystalline cellulose or any combination thereof, and are intended to be filled using a solution of the active ingredient in an organic solvent or mixture of organic solvents in which the active ingredient is soluble. Solvents may be heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethylketone, methylisobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, t-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl fumarate, formic acid, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2- dichloroethane, dichloromethane, 1,2-dimethoxyethane, N, N-dimethylacetamide, N, N-dimethylformar. dd, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, methylbutyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, tetrahydrofuran, toluene, xylene or a mixture of two or more of the solvents listed.

The invention comprises two methods of filling. The tablet bases can be immersed in an excess solution of the active substance in an organic solvent. In this case, each tablet in the same batch absorbs the same weight of the solution due to the capillary effect. According to another method, a solution of the active ingredient is added separately to each tablet with a suitable withdrawal, e.g. pipette so that the tablet absorbs all the amount of solution added. In both cases, repeatability of the active ingredient in each tablet is ensured. Drying of the tablets is followed, until the solvent used in the tablet is removed, which is below the permitted limit, or. valid pharmacopoeia. The pharmaceutical active substance must be soluble in an organic solvent or mixture of organic solvents to the extent that a single, two, three, or multiple filling process of the same tablet can provide a therapeutic dose in the tablet. The manufactured tablets, depending on the composition in aqueous buffer solutions, immediately disintegrate, so that the dissolution of the drug depends on its properties or decays, or dissolves very slowly and modifies the release

-6 the active substance in such a way that its dissolution is slowed down or controlled. The tablets of the invention may be of any color, texture or shape, e.g. round oval, biconcave, rectangular, square polygonal, etc. Their total weight is from 10 mg to 1000 mg, preferably from 50 mg to 500 mg.

Example A

The tablets are made by direct tableting of microcrystalline cellulose treated with SiO _{2 with a} diameter of 12 mm weighing 440 mg. Immerse the tablet in an organic solvent for a few minutes and determine whether it remains whole or decomposes.

Solvent Breakdown of tablets Ethyl acetate It does not fall apart Tetahydro furan It does not fall apart Hexane It does not fall apart Heptane It does not fall apart 1-propanol It does not fall apart 1-butanol It does not fall apart 2-butanol It does not fall apart Diethyl ether It does not fall apart Methyl ethyl ketone It does not fall apart Ethanol It's falling apart Methanol It's falling apart Acetone It's falling apart Dimethylsulfoxide It's falling apart

-7Example B

The tablets are made by direct tabletting of lactose monohydrate / SiCh / microcrystalline cellulose treated with S1O2 in a 30/20/50 ratio of 10 mm diameter 440 mg. Immerse the tablet in an organic solvent for a few minutes and determine whether it remains whole or decomposes.

Solvent Breakdown of tablets Ethyl acetate It does not fall apart Tetahydrofuran It does not fall apart Hexane It does not fall apart Heptane It does not fall apart 1-Propanol It does not fall apart 1-butanol It does not fall apart 2-butanol It does not fall apart Diethyl ether It does not fall apart Methyl ethyl ketone It does not fall apart Ethanol It does not fall apart Methanol It does not fall apart Acetone It's falling apart Dimethylsulfoxide It does not fall apart

-8Example C

The tablets are made by direct tableting of microcrystalline cellulose treated with S1O2 with a diameter of 10 mm weighing 440mg. The tablets were filled with immersion in a solution of ketoprofen in ethyl acetate (20% w / v concentration) for one minute and dried (0.7 bar pressure, 60 ° C temperature). The ketoprofen content of the tablet was determined by dissolving in ethanol and spectrophotometrically by determining the concentration at a wavelength of 257 nm.

The mass is empty Weight of the tablet and Calculated mass Between one mass pills ketoprofen of ketoprofen in a tablet of ketoprofen in a tablet (g) (g) (g) (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

The tablets are made by direct tableting of microcrystalline cellulose treated with S1O2 10 mm in diameter, weighing 240 and 455 mg filled with diclofenac by pipetting on each side with 75 microliters of diclofenac solution in tetrahydrofuran (20% w / v concentration). The diclofenac content of the tablet was determined by dissolution in methanol and spectrophotometrically by determining the concentration at a wavelength of 282 nm.

The mass is empty Weight of the tablet and Calculated mass Drop one mass pills diclofenac diclofenac in the tablet dicofenac in tablet (g) (g) (g) (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

-9Example E

Direct tableting produces tablets of 400 mg (50% silica gel + 50% lactose) and filled with ethanol solution of ketoprofen (7g / 15ml). After drying, they contain 40 mg ketoprofen tablets. Ketoprofen-filled tablets were dissolved for 24 h in chloride buffer, pH = 1.0 and 37 ° C. Under the same conditions, the pure ketoprofen powder (40 mg) is dissolved. The concentration of ketoprofen release from tablets and powder during dissolution was determined spectrophotometrically at a wavelength of 257 nm. The diagram of Figure 1 shows the dissolution of ketoprofen and ketoprofen powder from a tablet filled with ethanol solution in chloride buffer at pH = 1.0.

Example F

Direct tableting produces tablets of 400 mg (50% silica gel + 50% lactose) and filled with ethanol solution of ketoprofen (7g / 15ml). After drying, they contain 40 mg ketoprofen tablets. Ketoprofen-filled tablets were dissolved for 24 h in phosphate buffer, pH = 7.4 and 37 ° C. Under the same conditions, the pure ketoprofen powder (40 mg) is dissolved. The concentration of ketoprofen release from tablets and powder during dissolution was determined spectrophotometrically at a wavelength of 257 nm. The diagram of Figure 2 shows the dissolution of ketoprofen and ketoprofen powder from a tablet filled with ethanol solution in phosphate buffer with pH = 7.4.

Example G

Direct tableting produces tablets weighing 400 mg (50% silica gel + 50% lactose). The tablets are filled with an ethanol solution of ketoprofen [5g / 10ml] by immersion in an ethanol solution of ketorpofen, dried and refilled by immersion in an ethanol solution of the active substance. After each charge, the content of ketoprofen in the dissolution tablet is determined. The diagram in Figure 3 shows the ketoprofen content of the tablet after single and multiple fillings.

The tablets of the invention allow for the faster and cheaper development of a formulation for the manufacture of a medicament compared to conventional tablet manufacturing methods. Less equipment and fewer ingredients are needed to make tablets. There is no dusting or contamination of the apparatus involved in granulating and tabletting with the active ingredient, which makes the cleaning of the equipment less demanding than

-10Conventional tablet manufacturing methods where trace amounts of the active substance need to be removed. Energy consumption is also less compared to granulation since there is no evaporation of water which has a large evaporative heat.

Claims (8)

Patent claims 1. Porous active substance refill tablets, wherein the tablet bases are manufactured by known methods, characterized in that the pharmaceutical tablet bases consisting solely of excipients are used in pharmaceutics that are not soluble in organic solvents and in contact with them they do not decompose and are then filled with the active ingredient solution in an organic solvent and then the tablets are dried. Tablets according to claim 1, characterized in that the excipients are lactose and / or SiO ₂ and / or SiO ₂ treated microcrystalline cellulose in different proportions. Tablets according to claim 1, characterized in that the organic solvents in which the pharmaceutical substance is dissolved are heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-butanol, methylethylketone, methylisobutylketone, 2-methyl-1-propanol, pentane , 1-pentanol, 1propanol, 2-propanol, propyl acetate, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, t-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl fumarate, formic acid , acetonitrile, chloiobenzene, chloroform, cyclohexane, 1,2-dichloroethane, dichloromethane, 1,2-dimethoxyethane, N, N-dimethylacetamide, Ν, Ν-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formam id, hexane, methanol, methylbutyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine. , tetrahydrofuran, toluene, xylene or a mixture of two or more of the solvents listed. Tablets according to claim 1, characterized in that the powder mixture for tableting is added a slider prior to tableting. Tablets according to Claim 4, characterized in that the slider is Mg stearate. Tablets according to claim 1, characterized in that the tablets have a weight of from 50 mg to 1000 mg. A method of manufacturing a porous active substance refill tablet according to claims 1 to 5, characterized in that the tablet bases are immersed in an excess solution of the pharmaceutical substance in an organic solvent. A method of making a porous active substance re-filler tablet according to claims 1 to 5, characterized in that the pharmaceutical substance solution is added separately to each tablet with a suitable ejection, preferably pipetted so that the tablet absorbs the entire amount of solution added.