RU2039553C1 - Solid medicinal form of iphosphamide - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: this solid medicinal form designed for oral application in the form of capsules containing iphosphamide as active substance and microcrystalline cellulose or tablets containing about 0.04 to 0.4 percent by mass tricalciumphosphate taken per one part by mass (0.1 to 1.0) iphosphamide and 5 to 60 percent by mass of filler (per mass of single tablet), about 1.0 to 10.0 mass percent fluidity-control additive, 0.1 to 10.0 mass percent additive carrier capable of producing antisclerotic effect, and 0.1 to 80.0 mass percent of binder. EFFECT: more sophisticated medicinal preparation.

Description

 The invention relates to a solid dosage form for oral administration containing ifosfamide as the active substance: 3- (2-chloroethyl) -2- (chloroethylamino) -tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide. Ifosfamide is a drug like oxazaphosphorin with cytostatic activity.

Ifosfamide is a white crystalline powder highly hygroscopic substance having a melting point ^of 48-51 C. At temperatures below the melting point of ifosfamide begins to sinter, so it should be kept at the lowest possible temperatures. In addition, contact with moist air should be avoided. Ifosfamide dissolves to about 10 wt. in water. However, aqueous solutions can be stored for a limited time.

 Until now, the use of ifosfamide has been allowed only in the form of preparations for parenteral administration. Ifosfamide is available in the form of a sterile crystallizate in ampoules for injection in a package of 200-2000 mg. Before use, this sterile crystallizate must be dissolved in water for injection. The concentration of such a solution should not exceed 4%. The prepared solution can be used for intravenous injection. For short-term intravenous infusion, ifosfamide solution is dissolved in 500 ml of Ringer's solution or other similar infusion fluids. The duration of the infusion is usually about 30 minutes. However, it can last 1-2 hours. If injected 24 hours, ifosfamide solution is dissolved, for example, in 3 l of a 5% solution of dextrose and sodium chloride.

 Upon receipt and processing of ifosfamide, a number of problems arise.

 Upon receipt of sterile crystalline ifosfamide, a product is formed whose physical characteristics may be different. Different flowability of the obtained product, in particular, sharply negatively affects the accuracy of dosing or packaging.

 The processing of ifosfamide is further complicated by its hygroscopicity and low melting point. During prolonged storage, the sterile crystallizate sinter, as a result, its dissolution rate decreases. With the beginning of sintering, the pH and transparency of the resulting solution decreases and at the same time it turns yellow. Typically, such a drug is no longer suitable for therapeutic use.

 The main disadvantages associated with its use. Parenteral administration can only be carried out by qualified medical staff. For this purpose, the patient should be placed in a hospital or appear daily to undergo treatment. This is time consuming for both the staff and the patient.

 Obtaining a sterile solution for injection from dry matter due to harmfulness makes it necessary to take expensive protective measures for personnel. For patients, parenteral administration of the drug is an unpleasant procedure, since for its implementation it is necessary to make a painful injection, and connect the appropriate equipment for the duration of the infusion.

 The consequence of all these disadvantages is the need for oral preparations that do not have these disadvantages. With oral administration, outpatient treatment of patients is possible.

 However, all previous attempts to obtain solid preparations for oral administration ended in failure due to the physicochemical properties of ifosfamide. Medications in the form of soft gelatin capsules could not be obtained. Apparently, the active substance reacts with the capsule shell, which becomes solid, and as a result, the capsule no longer dissolves in the gastric juice. Likewise, numerous attempts to obtain tablets failed. The substance stuck to the dies of a tablet-making machine, the resulting tablets were too soft, the liquefied active substance, when compressed, partially splashed out of the matrix.

 Ifosfamide mixed with microcrystalline cellulose can fill hard gelatin capsules. In this case, there is no undesirable interaction of ifosfamide with the capsule shell. Although the capsule shell contains 12-15 wt. water, and ifosfamide is a hygroscopic and moisture-sensitive material, its hard gelatin capsule containing it can be stored for many years and even after such long storage the capsule shell dissolves in the gastric juice in a few minutes.

 Ifosfamide capsules in accordance with the invention contain, for example, 100-800, preferably 200-500 mg of ifosfamide.

 The contents of the capsule consists mainly of ifosfamide and microcrystalline cellulose. Along with these components, its composition may include small amounts of conventional fluidity-controlling and anti-adhesive additives. These flow control and anti-adhesive additives can be used both in relativity and in the mixture. The total content of such additives per 1 wt. including ifosfamide is, for example, 0.001-0.1, preferably 0.01-0.04 wt. h. As such fluidity-controlling and anti-adhesive additives, known additives can be used.

 In particular, magnesium stearate and other stearates, highly dispersed silicon dioxide, stearic acid, talc and polyglycols (for example, with a molecular weight of 4000-6000) can be used as such components.

 The preferred content of the fluidity adjusting additive is 0.002-0.02, most preferably 0.005-0.008, and the anti-adhesive additive is -0.004-0.08, most preferably 0.016-0.032 wt. hours for 1 wt. including ifosfamide.

 In addition, the contents of the capsule may include an excipient, for example, starch, cellulose, milk sugar, fructose, sucrose, mannitol, sorbitol, calcium phosphate; a binder, for example gelatin, cellulose, pectin, alginate, polyvinylpyrrolidone; a carrier, for example, alginate, carboxymethyl cellulose, polyvinylpyrrolidone, ultraamylopectin.

Highly dispersed silicon dioxide (for example, Aerosil ^® ), as well as magnesium stearate, can be used as a fluidity control additive.

The content of microcrystalline cellulose in capsules is usually 0.2-4, preferably 0.25-1, most preferably 0.3-0.35 wt. hours for 1 wt. including ifosfamide. The microcrystalline cellulose used must have a crystallinity degree characterized by a crystallinity index (the crystallinity index refers to the ratio of the crystalline fraction to the total crystalline and amorphous fractions. For crystalline cellulose with a particle size of about 50 μm, this index is, for example, 0.71.) 0.5-0.9, for example 0.7. The degree of polymerization of microcrystalline cellulose should be in the range of 200-300. In addition, the microcrystalline cellulose used must have an average grain size, for example of the order of 50, preferably less than 50 microns. It is desirable that it be less than 40, in particular of the order of 20 microns. It is preferable to use Avitzel ^® cellulose as microcrystalline cellulose, for example Avitzel ^® with a particle size distribution of less than 38 μm (Avitzel ^® PH 105) (this means that the average particle size of at least 90% of microcrystalline cellulose particles is less than 38 μm, preferably equal to 20 μm )

 In addition, a method has been developed for the preparation of tablets based on ifosfamide as an active substance, the combination of tricalcium phosphate and polyethylene glycol being the most suitable. Thanks to this method, it was for the first time possible to obtain such tablets by compression on a conventional tablet press.

 The physicochemical properties of ifosfamide do not allow tablets to be obtained from it by compression on conventional tablet making machines. All attempts to compress this active substance using known auxiliary additives, such as, for example, microcrystalline cellulose, lactose, starch, talc, finely divided silica, calcium hydrogen phosphate, have failed. And with the help of granulation, carried out in the usual way or in a fluidized bed, it was also not possible to obtain a mass from which tablets could be pressed easily and simply. In all cases, during the pressing process, the mass adhered to the die or die.

 Tablets in accordance with the present invention per 1 wt. including ifosfamide contains: 0.1-1.0 wt. including tricalcium phosphate and 0.04-0.4 wt. including polyethylene glycol (for example, with a molecular weight of 4000-6000) and, in addition (based on the weight of the tablet), 5-60 wt. filler and additives, regulating fluidity, 1-10 wt. carrier, 0.1-10 wt. additives providing an anti-adhesive effect, 0.1-80 wt. binder.

 For 1 wt. part of ifosfamide in accordance with the invention use, for example, 0.1-10 wt. including preferably 0.2-0.5, most preferably 0.25-0.30 wt. including tricalcium phosphate. Based on the weight of the tablet, the amount of tricalcium phosphate is, for example, 35, preferably 7-17.8, most preferably 9-1 wt.

 The content of polyethylene glycol is, for example, 0.04-0.4, preferably 0.1-0.2, most preferably 0.13-0.15 wt. hours for 1 wt. including ifosfamide. It is preferable to use polyethylene glycol with a molecular weight of 4000-6000, most preferably with a molecular weight of 6000. Based on the weight of the tablet, the content of polyethylene glycol is, for example, 1-14.0, preferably 3.5-7.5, most preferably 4.5-7 , in particular 4.5-6 wt. The weight ratio between tricalcium phosphate and polyethylene glycol is, for example, 1: 0.5.

 In addition to these components, tablets contain: a filler and a fluidity regulating additive in an amount of 5-60 wt. based on the weight of the tablet. As the filler, for example, starches, cellulose, lactose, sucrose, fructose, sorbitol, mannitol, calcium phosphate, calcium carbonate, calcium sulfate, carbonate or magnesium oxide can be used. These compounds are used in an amount of 5-60 wt. based on the weight of the tablet.

 As a fluidity regulating additive, for example, microcrystalline cellulose, lactose, polyglycols, starches, cellulose, talc, talc siliconisate, arachinate or calcium stearate, cetyl alcohol, stearyl alcohol, myristyl alcohol, stearic acid, lauric acid can be used. In the event that the fluidity regulating additive does not simultaneously play the role of a filler, it is used in an amount of 0.5-10 wt. based on the weight of the tablet.

 Carriers: for example alginates, starches (for example, corn starch), pectins, carboxymethyl cellulose, polyvinylpyrrolidone, ultraamilopectin, bentonite. Its content is 1-10 wt. based on the weight of the tablet.

 An anti-sticking agent, for example glycols, talc, talc siliconisate, talc stearicate, calcium stearate, aluminum stearate, stearic acid. Its content is 0.1-10 wt. based on the weight of the tablet.

 A binder, for example gelatin, cellulose ether, amylose, pectin, cellulose, dextrose, polyglycol, tragacanth. Its content is 0.1-80 wt. based on the weight of the tablet.

 Preferably, the tablets, in addition to ifosfamide, tricalcium phosphate and polyethylene glycol, contain the following materials: microcrystalline cellulose in an amount of 0.1-1.2, preferably 0.4-1.0, most preferably 0.70-0.90 wt. calculated on one weight part of ifosfamide or 7-43, preferably 15-35 wt. based on the weight of the tablet; lactose in an amount of 0.15-1.0, preferably 0.24-0.68, most preferably 0.30-0.40 wt. hours per one weight part of ifosfamide or 5.0-36, preferably 8.5-25 wt. based on the weight of the tablet; corn starch in an amount of 0.02-0.24 wt. including preferably 0.05-0.20, most preferably 0.1-0.15 wt. hours per one wt. including ifosfamide or 0.7-8.5, preferably 2.0-6.5 wt. based on the weight of the tablet; talc in an amount of 0.02-0.30, preferably 0.06-0.20, most preferably 0.07-0.09 wt. hours per one wt. including ifosfamide or 0.70-10, preferably 2-6.5 wt. based on the weight of the tablet; magnesium stearate in an amount of 0.004-0.2, preferably 0.02-0.12, most preferably 0.035-0.05 wt. hours per one wt. including ifosfamide or 0.1-7.2, preferably 0.7-4.5 wt. based on the weight of the tablet.

 Both tablets and capsules can be coated in a known manner. This may be a water-soluble, swellable, water-soluble or gastric juice resistant coating applied from an aqueous dispersion or aqueous solution, or from a dispersion solution in an organic solvent such as, for example, ethanol, isopropanol, acetone, ether, dichloromethane, methanol.

Capsules and tablets are prepared at a temperature, for example 15-26, preferably 18-22 ^C. The relative humidity in the production rooms should not exceed 40%
Examples illustrate a specific embodiment of the invention.

To obtain proposed in accordance with the invention, solid dosage forms based on ifosfamide for oral administration of 1 wt. including ifosfamide is mixed at 15-30 ^about With 0.1-4, preferably 0.2-4, most preferably 0.25-1 wt. including microcrystalline cellulose and, if desired, with small amounts of fluidity regulating and anti-sticking additives until a hemogenous mixture is formed, and capsules are filled with this mixture or 1 wt. including ifosfamide with 0.1-1.0 wt. including tricalcium phosphate, 0.04-0.4 wt. including polyethylene glycol and 0.15-2, preferably 0.5-1.5, most preferably 1-1.3 wt. including filler and regulating the fluidity of the additive, 0.03-0.5, preferably 0.05-0.4, most preferably 0.08-0.2 wt. including carrier, 0.003-0.5, preferably 0.01-0.4 most preferably 0.05-0.2 wt. including additives that have an anti-adhesive effect, and 0.003-3, preferably 0.01-2, most preferably 0.1-1 wt. including a binder to form a homogeneous mixture. Then tablets are pressed from this mixture and, if desired, a conventional coating is applied to the resulting capsules or tablets.

 PRI me R 1. Containing ifosfamide mass for filling capsules.

 According to the proposed method, the mass for filling capsules is obtained, for example, as follows.

 To obtain 12,000 capsules with an active ingredient content of 250 mg, for example, 3.0 kg of ifosfamide, 1.002 kg of microcrystalline cellulose and 0.018 kg of highly dispersed silicon dioxide are sieved through a sieve with a mesh size of 0.8 mm and the mixture is stirred for 4 minutes in a mixer. After that, 0.06 kg of magnesium stearate (sifted through a sieve with a mesh size of 0.8 mm) was added to the mixture and the mixture was stirred for another minute. The finished mixture is Packed on a machine for the manufacture of capsules with formatted nozzles N 1 in hard gelatin capsules of size N 1 so that approximately 340 mg of mass is contained in each capsule.

 To obtain 20,000 capsules with an active ingredient content of 500 mg, they are sieved through a sieve with a mesh size of 0.8 mm, for example, 10.0 kg of ifosfamide, 3.34 kg of microcrystalline cellulose and 0.06 kg of finely divided silica and the mixture is stirred for 4 minutes in the mixer. Then, 0.2 kg of magnesium stearate (sifted through a sieve with a mesh size of 0.8 mm) was added to this mixture and the mixture was stirred for one minute. The finished mass is Packed on a machine for the manufacture of capsules with formatted nozzles N 00 in hard gelatin capsules of size 00 so that each capsule contains about 680 mg of mass. As microcrystalline cellulose, for example, an Avitel PH 105 is used, which has a certain range of particle size distribution and is a filler with good fluidity, which can successfully play the role of a binder.

 To obtain capsules that are resistant to the action of gastric juice, for example, 2500 capsules of size 1 containing the active substance (ifosfamide) 250 mg are coated with 3000 g of a suspension in an organic solvent (isopropanol). 3000 g of suspension contain 1440 g of anionic polymerizate of methacrylic acid and its esters with an average molecular weight, for example, 150,000, with the addition of conventional plasticizers, 18 g of 1,2-propanediol, 36 g of magnesium stearate and 1506 g of isopropanol.

As the copolymerizate of methacrylic acid and methyl methacrylate, for example, eudragit L ^® in particular in the form of a 12.5% solution in isopropanol (12.5% eudragit ^® ) can be used. Such copolymerizates are soluble in the medium from neutral to slightly alkaline due to the formation of alkali metal salts.

 PRI me R 2. Obtaining ifosfamide tablets.

Tablets with an active substance content of 250 mg may have, for example, the following composition:
One tablet weighing 700 mg contains, mg: Ifosfamide 250 Fine tricalcium phosphate 70 Microcrystalline cellulose 200 Lactose 85 Polyglycol 6000 85 Corn starch 30 Talc 20 Magnesium stearate 10
To prepare the mass for 1500 tablets, 375 g of ifosfamide, 105 g of finely divided tricalcium phosphate, 300 g of microcrystalline cellulose, 127.5 g of lactose, 52.5 g of polyglycol 6000, 45 g of corn starch, 80 g of talc are passed through a sieve with a mesh size of 0, 8 mm and mix the mixture for 15 minutes in a suitable mixer. Then, 15 g of magnesium stearate sieved in the same manner are added to the mixture and it is stirred for another 2 minutes. From the prepared mass, tablets are compressed in a suitable tablet press.

 To obtain tablets resistant to the action of gastric juice, 1050 g of tablets are coated with, for example, 500 g of an aqueous dispersion of the following composition.

30D 55,000 Вода 38,044
_______
100,000
Эвдрагит L^® представляет собой водную дисперсию сополимеризата анионного характера на основе метакриловой кислоты и этилакрилата. Соотношение между свободными карбоксильными группами и эфирными группами в нем составляет примерно 1:1, а средний молекулярный вес равен около 250000.100 g of an aqueous dispersion contain, g: Polyglycol 6000 1,600 Titanium dioxide 1,100 Yellow iron oxide 0,156 Talc 4,000 Dimethylpolysiloxane 0,100 Eudragit L

30D 55,000 Water 38,044
_______
100,000
Eudragit L ^® is an aqueous dispersion of an anionic copolymerizate based on methacrylic acid and ethyl acrylate. The ratio between free carboxyl groups and the ester groups in it is about 1: 1, and the average molecular weight is about 250,000.

 The film-forming solution is sprayed, for example, using equipment commonly used for this purpose, in which the solvent and dispersant are continuously removed by drying.

Claims (1)

 SOLID MEDICINAL FORM OF IFOSFAMIDE, characterized in that the powder contains, by weight. including the active substance and microcrystalline cellulose 1 - 0.2 4 to fill hard gelatin capsules, and the tablets contain, wt. h Ifosfamide 1.0
Tricalcium phosphate 0.1 1.0
Polyethylene glycol 0.04 0.4
and also excipients based on the weight of the tablet, wt. Moving 5 60
Loosening 1 10
Lubricants 0.1 10
Binders 0.1 80