Methods for preparing ergot alkaloids pharmaceutical compositions with prolonged effect characterizing with improved bioavailability and compositions comprising indicated alkaloids

FIELD: organic chemistry, natural compounds, pharmacy.

SUBSTANCE: method involves mixing ergot derivative or its mixture with pharmaceutically acceptable hydrophilic swelling substance or its mixture and with one or some pharmaceutically acceptable vehicles. Derivative of ergot has the following formula: wherein R1 means hydrogen or halogen atom; R2 means hydrogen atom or (C1-C4)-alkyl; R3 represents isopropyl, sec.-butyl, isobutyl or benzyl; R4 represents methyl, ethyl or isopropyl; R5 means hydrogen atom; R6 means hydrogen atom or methoxy-group, or R5 and R6 in common correspond to the additional bond. The ratio of ergot derivative to swelling agent = (1-0.5):(1-10). Pharmaceutical composition containing the substance prepared by above indicated method comprises from 5 to 80 mg of ergot derivative in its ratio to swelling agent from 1:0.5 to 1:10. Invention provides realization the indicated designation.

EFFECT: improved methods for preparing, valuable properties of compositions.

6 cl, 6 tbl, 1 dwg, 8 ex

 

The technical field of the invention

This invention relates to methods of producing pharmaceutical compositions of ergot alkaloids with slow release and, in particular, to methods for producing pharmaceutical compositions of ergot alkaloids slow release, which is characterized by improved bioavailability.

Prerequisites to the creation of inventions

Generally ergot alkaloids can be classified according to their different structure, for example Ergoline, derivatives of lysergic acid, peptide ergot alkaloids and digidrirovannye peptide ergot alkaloids. Clinical use of ergot alkaloids and their derivatives includes, among other things, the treatment of Parkinson's disease, headaches, associated with migraine, hyperprolactinemia, cerebrovascular disorders.

There are plenty of ergot alkaloids and their derivatives. For example, in U.S. patent No. 3896228 issued Richardson, discusses the use of ergot alkaloids to increase urination and urine pH. In U.S. patent No. 3987173 issued Borredon, it is proposed to use certain mixture of vincamine and of ergot alkaloids for the treatment of circulatory disorders. In U.S. patent No. 4229451 issued by Fehr et al., describes derivatives ergopeptine used as venoconstrictor and venotonic. In the patent the SHA No. 4315937, issued Maclay et al., discusses the LPV and its application for the treatment of small brain dysfunction. In U.S. patent No. 4366145 issued Stoopak et al., describes a soft gelatin capsule, filled in the center with a solution of liquid alkaloid of ergot. In U.S. patent No. 4440722 issued Djorjevic et al., offered medicines containing salts ergotamine, ergosine, ergocristine, ergocryptine and ergocornine used to treat hypertension, congestive heart failure, cardiac arrhythmia, or headache. In U.S. patent No. 4462983 issued Azria et al., discusses the use of certain peptide ergot adapted for nasal or pulmonary administration.

Pharmacological effects of ergot alkaloids are varied and complex, but, as it turned out, implemented primarily as a result of the effects of alkaloids on adrenergic, dopaminergic and serotonergic receptors. Range of effects depends on the substance, dose, species, tissue, and experimental or physiological conditions. Generally ergot alkaloids are characterized by unstable absorption and intense "first pass metabolism in the liver with extensive biotransformation. More precisely, the absorption of ergot alkaloids in the gastrointestinal tract is low due to intensive is Echinacea "first pass metabolism" and sometimes unstable. In addition, occasionally the use of ergot alkaloids may be associated with adverse events, particularly vascular and cardiac effects. Drugs such as ergot alkaloids, which are exposed to high hepatic clearance may require higher doses to maintain blood concentrations above the minimum effective concentration for a sufficient period of time to provide the desired pharmacological effect. However, if you used a regular system of drug delivery, the surge absorption of medicines, which takes place after its introduction, can induce blood concentrations that exceed the minimum toxic concentration. One way around this harmful effect is the use of lower dosages with often repeated by taking medication. However, frequent dosing is not ideal because of the inconvenience, increasing costs and the increased likelihood that the patient will forget to take the appropriate number of doses. Another way to maintain the concentration of drug on a limited therapeutically active level is the introduction of a drug, using a delivery system with prolonged release of the drug.

Delivery system with prolonged release of drugs include any drug delivery system tools, which successfully carried out the slow release of drug over an extended period of time. There are two main types of systems with a long release: controlled release and prolonged release. Systems for controlled release maintain constant levels of the drug in the tissues or target cells. The prolonged release system is not able to maintain a constant level of drug, but nevertheless prolong the presence of therapeutic levels of drug in blood or tissue for a long period of time.

When creating delivery systems with a long release should consider many variable factors, including the method of delivery of the medicinal product, the type of delivery system, the special properties of a medicinal product which is introduced, and the bioavailability of the drug. Delivery systems with slow release intended for a number of different medicines. For example, in U.S. patent No. 4389393 issued by Schor et al., offers therapeutic compositions with slow release based on high is the molecular hydroxypropylmethylcellulose. In U.S. patent No. 5069911 issued by Züger, proposed composition with controlled release for oral administration 9,10-dihydrochloride ergot, in U.S. patent No. 5128142 issued by Mulligan et al., describes the composition of controlled release, which includes absorbed a mixture of pharmaceutically acceptable active ingredient and inactive substances absorbed on the cross crosslinked polymer.

At that time, as in the above-mentioned patents provide delivery systems with slow release, which can provide a slow release of certain medications over a long period of time, they are not provided with such a system, which also maintains or increases the bioavailability introduced drugs compared with conventional delivery systems.

Summary of invention

Therefore, the aspect of the present invention is to provide a delivery system for drugs with prolonged his release, which maintain or increase the bioavailability introduced drugs compared with conventional delivery systems.

Another aspect of the present invention is to provide methods of making such delivery systems.

According to this invention, these and other and what aspects are provided by a method for improving the bioavailability of the derivative of ergot, which includes a combination of a derivative of ergot, or mixtures thereof, with pharmaceutically acceptable hydrophilic swelling agent, or its mixture with one or more pharmaceutically acceptable excipients.

According to this invention, the bioavailability is at least equal bioavailability ergot derivative, or mixtures thereof, is introduced using normal shipping method.

In a preferred aspect of the ergot derivative has the formula

in which:

R1means hydrogen or halogen,

R2means hydrogen or C1-C4alkyl,

R3means isopropyl, sec-butyl, isobutyl or benzyl,

R4represents methyl, ethyl, isopropyl and their mixtures and simple air,

R5means hydrogen and

R6means hydrogen or methoxy, or

R5and R6together represent an additional bond, and mixtures thereof.

According to this invention also provides pharmaceutical composition. The composition has a bioavailability that is at least equal bioavailability ergot derivative, or mixtures thereof, is introduced using conventional delivery method.

Therefore, according to this invention, the methods and pharmaceutical compositions can provide features prolongirovannogo, at the same time improving the bioavailability of ergot derivatives.

Brief description of drawing

The drawing is a graph showing plasma concentration α-dihydroergocryptine depending on time after a single oral administration of 10 mg α-dihydroergocryptine introduced in the form of conventional tablets or in the form of a slow release tablets prepared according to this invention as described in examples 5 or 6.

Detailed description of preferred aspects

The invention will be described in more detail below, which represent preferred aspects of the invention. However, this invention may be embodied in many different forms and should not be construed as limited to the aspects set forth in the description; rather, these aspects are presented with the fact that this statement would be a perfect and complete and fully conveys the idea of the invention to specialists in this field.

This invention provides a composition derivatives of ergot slow release, which is characterized by improved bioavailability compared to conventional compositions. The composition of the prolonged action of the present invention contains a derivative of ergot or a mixture of pharmaceutically acceptable swellable substance, or mixture, and one or several flats which are pharmaceutically acceptable excipients. Used in the description, the term "bioavailability" is defined as the total number of drugs systemically available for a period of time. Bioavailability can be determined by measuring the total systemic concentrations of drugs during the period of time after administration of the composition of prolonged action of this invention and after the introduction of the compositions of the regular release. Improved bioavailability is defined as the increase in the area under the curve" (AUC). AUC is an integrated indicator of systemic concentrations of drugs within the time in units of mass/volume. After administration of the dose, AUC from time of receipt of the medication in the body until its complete removal from the body is an indicator of the impact on patient medications.

Derivatives of ergot of this invention can be a variety of derivatives of ergot, well-known experts in this field. Preferably derivatives of ergot are the alkaloids of ergot. The preferred ergot alkaloids are peptide ergot alkaloids and digidrirovannye peptide ergot alkaloids. Particularly preferred ergot alkaloids have the formula:

R1means adored or halogen,

R2means hydrogen or C1-C4alkyl,

R3means isopropyl, sec-butyl, isobutyl or benzyl,

R4represents methyl, ethyl, isopropyl and their mixtures and simple air,

R5means hydrogen and

R6means hydrogen or methoxy, or

R5and R8together represent an additional bond, and mixtures thereof, or mixtures thereof.

If R1means halogen, it preferably represents bromine.

Preferred compounds of formula I are compounds in which R1, R5and R6mean hydrogen, R2means methyl, a R4corresponds to the isopropyl or stands, provided that R4means only methyl when R3represents benzyl.

Particularly preferred compounds in which R2means methyl, a R1, R5and R6mean hydrogen, represent α-dihydroergocryptine (R4= isopropyl, R3= isobutyl), β-dihydroergocryptine (R4= isopropyl, R5= sec - butyl), dihydroergocornine (R3= R4= isopropyl), dihydroergocristine (R4= isopropyl, R3= benzyl) and digidroergotamin (R4= methyl, R3= benzyl), together with their salt forms. The preferred compound in which R1means bromine, represents bromkriptin, 2= methyl, R3= isobutyl, R4= isopropyl and R5and R6mean secondary link. Acceptable salt forms are salts of pharmacologically acceptable acids, for example, methanesulfonate, maleate and tartrate. The most preferred compound is dihydroergocryptine, usually used in the form of nelfinavir. It is intended for the treatment of Parkinson's disease, hyperprolactinemia, and migraines. The drug can enter twice a day with a daily dose of from about 10 to 60 mg, preferably about 20-40 mg.

Pharmaceutically acceptable swellable substances of this invention are typically hydrophilic polymers, such as resin, ethers, cellulose materials derived from proteins. Preferably these hydrophilic polymers may include hydroxyethylcellulose, polyvinyl alcohols, polyoxyethyleneglycol and poloxamer. Preferred hydroxyethylcellulose include methylcellulose, carboxymethylcellulose, hydroxypropylcellulose and hypromellose.

The most preferred hydrophilic substance, which help the swelling is hydroxypropylcellulose. Hydroxypropylmethylcellulose that can be used in this invention include Metozel CM® and IU the Ouzel CM®, both commercially supplied by firm use of West Point, Pennsylvania. Metozel CM® and Metozel CM® contain 19-24 wt.% methoxyl and 4-12 wt.% hydroxypropyl. Metozel CM® 2% aqueous solution has a viscosity of 4000 SP and the average molecular weight 89000, while Metozel CM® in the same conditions has a viscosity of 15000 SP and the average molecular weight 124000.

The compositions of this invention also contain fillers. In General, the fillers include lubrication, suspendresume substances, binders, diluents, flavoring agents, dyes, dispersing agents and wetting agents, the use of which is well known to specialists in this field. In particular, acceptable fillers are fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; preparations of cellulose, such as microcrystalline cellulose, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum and/or polyvinylpyrrolidone (PVP); and lubricating agents such as magnesium stearate.

The compositions of this invention preferably contain from about 5 to 80 mg of peptide alkaloids of ergot. The ratio of peptide alkaloid of ergot to swelling substance is preferably from about 1:0.5 to 1:10, more preferably from about 1:2 to 1:8. The ratio di is hidroelectrica to swelling substance is from about 1:0.5 to 1:5, more preferably from about 1:1 to 1:4. The ratio of peptide alkaloid of ergot to the fillers is preferably from about 1:3 to 1:100, more preferably from 1:5 to 1:80 and most preferably from about 1:10 to 1:50.

The compositions of this invention provide increased bioavailability compared with other compositions with prolonged action. More importantly, the compositions of this invention provide increased bioavailability compared to conventional compositions. Preferably, the bioavailability of the compositions of the present invention above, at least about 5%, more preferably at least 15% and most preferably above at least about 25%, than the bioavailability of conventional compositions.

The compositions of this invention can be prepared according to conventional methods by mixing together the medicinal product and all of the fillers, in addition to lubrication, to obtain mixed powder. The powder is mixed with a lubricant and the resulting powder was pressed to form tablets.

The following examples are intended to illustrate this invention and should not be construed as a limitation. In the above examples, "mg" means milligrams, "ng" means nanogram, "RG" means the peak of the gram, "ml" means milliliter, "mm" means millimeter, "°" means degrees Celsius, "M" means secondary, "SD" stands for standard deviation, "MPa·s" millipascal·sec, "pvp" means polyvinylpyrrolidone, "h" means hour and "kp" means kilopond (kiloponds).

Examples 1-7. Comparison of the release characteristics of the compositions of the present invention with the release characteristics of conventional compositions

EXAMPLE 1

Tablets with prolonged action, containing 20 mg α-dihydroergocryptine

Composition each tablet

α-Dihydroergocryptine 20.0 mg

Cellactose® 203,0 mg1

Metozel CM® 25.0 mg2

Syloid 244® 1.2 mg3

Magnesium stearate 0.8 mg

Note: 1. Containing 75% lactose and 25% microcrystalline cellulose, commercially supplied by the company Meggle GmbH of Wasserburg, Germany.

2. The hypromellose USP type 2208; 15000 MPa·sec, commercially supplied by the company use of West Point, Pennsylvania.

3. Silicon dioxide is commercially supplied by the company W.R. Grace of Baltimore, Maryland.

Experimental method

Tablets (250 mg)containing 20 mg (8%) α-dihydroergocryptine, was obtained with 80% Cellactose® as directly compressible filler, 10% Metosulam KM® swelling of the polymer controls the release of 1.2% Silodam 244® as freely current wishes is in, and 0.8% magnesium stearate as a lubricant. Drug and all the fillers, in addition to lubrication, sift together the geometric principle manually using a sieve, and then mixed by mixer model in the turbula for 10 minutes After addition of magnesium stearate and the mixture was mixed for another 5 minutes For pressing used rotary 8-local laboratory press with automatic feed of the powder container and devices (12×5 mm).

Testing tablets

Used standard pharmaceutical testing methods and equipment to determine the following:

Hardness: average of 18.6 kp (Schleuniger 4M)

Friability: of 0.081%

The dissolution test according to USP XXIII, R, device 2, 1000 ml H2O, 50 rotations/min:

Time (hours)% Release α-dihydroergocryptine (M+/-SD)
0,512,7+/-0,5
123,8+/-1,4
232,6+/-3,0
455,1+/-6,0
672,2+/-4,5
884,7+/-6,3

Conventional tabletting composition 20 mg α-dihydroergocryptine had the following composition: α-dihydroergocryptine 20.0 mg lactose 148 mg; microcrystalline cellulose 70 mg; crosscarmellose 6 mg; teart magnesium 4 mg; and polyvinylpyrrolidone 2 mg of the dissolution Study was performed under the same conditions as for the composition of prolonged action of the present invention described in this example, and resulted 96,3+/-3,6% release α-dihydroergocryptine after 0.5 hours

EXAMPLE 2

Tablets with prolonged action, containing 20 kg α-dihydroergocryptine

Composition each tablet

α-Dihydroergocryptine 20.0 mg

Metozel CM® 13.2 mg1

Sodium CMC and 26.8 mg

Lactose 48,0 mg

PVP K30 of 6.7 mg

Talc 4, 0 mg

Magnesium stearate 1.3 mg

Note: 1. The hypromellose USP type 2208; 4000 MPa·sec, commercially supplied by the firm use of West Point, Pennsylvania.

Experimental method

Tablets (120 mg)containing 20 mg (16,7%) α-dihydroergocryptine, received and tested in accordance with methods described below. The composition was obtained with 40% lactose as diluent, 11% of Methocel CM® and 22.3% sodium CMC (medium viscosity) as swellable polymers that control the release of 5.6% PVP as a binder, 3.3% of talc as anticlimaxes substances and 1.1% of magnesium stearate as lubricant.

Received a 10% aqueous solution of PVP. The medicinal substance, the diluent and the polymer roughly mixed. An aqueous solution of PVP was added to the powder mixture for the formation of wet mass, which last is therefore sieved through a sieve of 8 mesh. The wet granules were dried at 60°C, then sieved through a sieve of 16 mesh. After adding talc and magnesium stearate and the mixture was mixed for five minutes in a V-mixer. For pressing used rotary 8-local laboratory press with automatic feed powder and flat fixtures, 7 mm

Testing tablets

Used standard pharmaceutical testing methods and equipment to determine the following:

Hardness: average 11,2 kp (Schleuniger 4M)

Friability: 0,12%

The dissolution test according to USP XXIII, R, device 2, 1000 ml H2O, 50 rotation/min:

Time (hours)% Release α-dihydroergocryptine (M+/-SD)
0,512,9+/-3,6
120,8+/-6,3
222,7+/-6,9
435,9+/-7,7
647,6+/vs.-7.9bn
8to 58.2+/-10,1
1268,4+/-8,0

Conventional tabletting composition 20 mg α-dihydroergocryptine had the same composition as in example 1. The dissolution study was performed under the same conditions as for the composition of prolonged action of the present invention described in this example, and resulted 98,1+/5,2% release α -dihydroergocryptine after 0.5 hour.

EXAMPLE 3

Tablets with prolonged action, containing 40 mg α-dihydroergocryptine

Composition each tablet

α-Dihydroergocryptine 40,0 mg

Lactose DCL11® 92,5 mg1

Avicel RN® 76,0 mg2

Metozel CM® 37.5 mg3

Magnesium stearate 4.0 mg

Note: 1. Dried spray lactose supplied by the company Meggle GmbH of Wasserburg, Germany.

2. Microcrystalline cellulose is commercially supplied by the company FMC Corporation, Pharmaceuticals Division, of Philadelphia, Pennsylvania.

3. The hypromellose USP type 2208, 4000 MPa·s commercially supplied by the company use of West Point, Pennsylvania.

Experimental method

Tablets (250 mg)containing 40 mg (16%) α-dihydroergocryptine, received and tested in accordance with methods described below. The song was received with 37% lactose and 30.4% of microcrystalline cellulose as a directly compressible fillers, 15% of Methocel KM®swelling of the polymer controls the release, and 1.6% of magnesium stearate as a lubricant.

Drug and all the fillers, in addition to lubrication, sift together the geometric principle manually using a sieve, then mixed with the turbula mixer for 10 minutes After addition of magnesium stearate and the mixture was mixed for another 5 minutes For pressing use is whether the rotor 8-local laboratory press with automatic feed of the powder container and devices (12× 5 mm).

Testing tablets

Used standard pharmaceutical testing methods and equipment to determine the following:

Hardness: average of 14.9 kp (Schleuniger 4M)

Friability: 0,072%

The dissolution test according to USP XXIII, R, device 2, 1000 ml H2O, 50 rotations/min:

Time (hours)% Release α-dihydroergocryptine (M+/-SD)
0,512,5+/and-0.6
122,1+/-1,4
235,9+/-3,0
4to 58.2+/-4,9
674,4+/-5,4
884,0+/is 6.2

Conventional tablet composition containing 40 mg α-dihydroergocryptine, had the following composition: α-dihydroergocryptine 40,0 mg; lactose 128 mg; microcrystalline cellulose 70 mg; croscarmellose 6 mg; magnesium stearate 4 mg; and polyvinylpyrrolidone 2 mg of the dissolution Study was performed under the same conditions as for the composition of prolonged action of the present invention described in this example, and received in the result of 93.3+/-5,0% release α-dihydroergocryptine after 0.5 hour.

EXAMPLE 4

Slow release tablets containing 40 kg α-dihydroergocryptine

Composition each tablet

αDigue is dragonriding 40,0 mg

Lactose DCL11® 105,0 mg1

Avicel RN® 76,0 mg2

The carbopol R® 25.0 mg3

Magnesium stearate 4.0 mg

Note: 1. Dried spray lactose

commercially supplied by the company Meggle GmbH of Wasserburg, Germany.

2. Microcrystalline cellulose is commercially supplied by the company FMC Corporation, Pharmaceuticals Division of Philadelphia, Pennsylvania.

3. Carbomer commercially supplied by BF Goodrich company of Cleveland, Ohio.

Experimental method

Tablets (250 mg)containing 40 mg (16%) α-dihydroergocryptine, received and tested in accordance with methods described below. The song was received with 42% lactose and 30.4% of microcrystalline cellulose as a directly compressible fillers, 10% carbomer, swelling of the polymer controls the release, and 1.6% of magnesium stearate as a lubricant.

Drug and all the fillers, in addition to lubrication, sift together the geometric principle manually using a sieve, then mixed with the turbula mixer for 10 minutes After addition of magnesium stearate and the mixture was mixed for another 5 minutes For pressing used rotary 8-local laboratory press with automatic feed of the powder container and devices (12×5 mm).

Testing tablets

Used standard pharmaceutical methods of testing and equipment, h is usually used to determine the following:

Hardness: the average value of 13.2 kp (Schleuniger 4M)

Friability: 0,2%

The dissolution test according to UPS XXIII, p.1792, device 2, 1000 ml H2O, 50 rotation/min:

Time (hours)% Release α-dihydroergocryptine (M +/- SD)
0,55,5+/--0,9
111,2+/-2,0
219,6+/-6,1
430,0+/-7,1
642,5+/-3,3
856,2+/-4,9

Conventional tabletting composition 20 mg α-dihydroergocryptine had the same composition as in example 3. The dissolution study was performed under the same conditions as for the composition of prolonged action of the present invention described in this example, and resulted 97,7+/-6,0% release α-dihydroergocryptine after 0.5 hour.

EXAMPLE 5

Tablets with prolonged action, containing 10 mg α-dihydroergocryptine

Composition each tablet

α-Dihydroergocryptine 10.0 mg

Cellactose® 184,3 mg1

Metozel CM® 22,0 mg2

Metozel CM® 9.7 mg3

Sodium-SMS 2.0 mg4

Talc 20.0 mg

Magnesium stearate 2.0 mg

Note: 1. Composed of 75% lactose and 25% microcrystalline cellulose, commercially supplied encourage company is Meggle GmbH of Wasserburg, Germany.

2. The hypromellose USP type 2208; 4000 MPa·sec, commercially supplied by the company use of West Point, Pennsylvania.

3. The hypromellose USP type 2208; 15000 MPa·sec, commercially supplied by the company use of West Point, Pennsylvania.

4. Medium viscosity.

Experimental method

Tablets (250 mg)containing 10 mg (4%) α-dihydroergocryptine, received and tested in accordance with methods described below. The composition received from 73.3% Cellactose®, as directly compressible filler, 8.8% of Methocel CM® 3.9% Methocel CM® and 0.8% sodium CMC as swellable polymers that control the release, and 8% of talc as anticlimaxes substance, and 0.8% of magnesium stearate as a lubricant.

Drug and all the fillers, in addition to lubrication, sift together the geometric principle manually using a sieve, then mixed with the turbula mixer for 10 minutes After addition of magnesium stearate and the mixture was mixed for another 5 minutes For pressing used rotary 8-local laboratory press with automatic feed of the powder container and devices (12×5 mm).

Testing tablets

Used standard pharmaceutical testing methods and equipment to determine the following:

Hardness: average of 19.1 kp (Schleuniger 4M)

Friability: 0,26%

The dissolution test according to USP XXIII, R, device 2, 500 ml of 0.01 N. Hcl, 50 rotations/min:

Time (hours)% Release α-dihydroergocryptine (M +/- SD)
0,514,8+/-1,0
123,6+/-1,5
238,2+/-1,6
460,9+/-1,1
678,5+/-3,9
889,3+/-4,4
1298,7+/-3,8

Conventional tabletting composition 10 mg α-dihydroergocryptine had the following composition: α-dihydroergocryptine 10 mg; lactose 158 mg; microcrystalline cellulose 70 mg; crosscarmellose 6 mg; magnesium stearate 4 mg; and polyvinylpyrrolidone 2 mg of the dissolution Study was performed under the same conditions as for the composition of prolonged action of the present invention described in this example, and received as a result of a 96.9+/-4,8% release α-dihydroergocryptine after 0.5 hour.

EXAMPLE 6

Slow release tablets containing 10 mg α-dihydroergocryptine

Composition each tablet

α-Dihydroergocryptine 10.0 mg

Cellactose® 216,0 mg1

Metozel CM® 15,0 mg2

Metozel CM® 5.0 mg3

Sodium-SMS 2.0 mg4

Magnesium stearate 2.0 mg

the note: 1.

Composed of 75% lactose and 25% microcrystalline cellulose, commercially supplied by the company Meggle GmbH of Wasserburg, Germany.

2. The hypromellose USP type 2208; 4000 MPa·sec, commercially supplied by the company use of West Point, Pennsylvania.

3. The hypromellose USP type 2208; 15000 MPa·sec, commercially supplied by the company use of West Point, Pennsylvania.

4. Medium viscosity.

Experimental method

Tablets (250 mg)containing 10 mg (4%) α-dihydroergocryptine, received and tested in accordance with methods described below. The song was received with 86.4% of Cellactose® as directly compressible filler 6% Methocel CM®, 2% Methocel CM® and 0.8% sodium CMC as swellable polymers that control the release, and 0.8% of magnesium stearate as a lubricant.

Drug and all the fillers, in addition to lubrication, sift together the geometric principle manually using a sieve, then mixed with the turbula mixer for 10 minutes After addition of magnesium stearate, and the mixture was mixed for another 5 minutes For pressing used rotary 8-local laboratory press with automatic feed of the powder container and devices (12×5 mm).

Testing tablets

Used standard pharmaceutical methods of testing and the equipment that is to determine the following:

Hardness: average 16,1 kp (Schleuniger 4M)

Friability: 0,16%

The dissolution test according to USP XXIII, R, device 2, 500 ml of 0.01 N. Hcl, 50 rotations/min:

Time (hours)% Release α-dihydroergocryptine (M +/- SD)
0,524,7+/of-2.1
137,7+/-2,8
958,3+/-3,2
482,6+/-3,9
692,9+/-3,6
897,6+/-1,8
12100,00+/-1,7

Conventional tabletting composition 10 mg α-dihydroergocryptine had the same composition as in example 5, and the dissolution study was performed under the same conditions as for the composition of prolonged action of the present invention described in this example, and received in the 93,7+/-3,1% release α-dihydroergocryptine after 0.5 hour.

EXAMPLE 7

Slow release tablets containing bromkriptin, 5 mg

Composition each tablet

Bromkriptin 5.0 mg

Cellactose® 189,3 mg1

Metozel CM® 22,0 mg2

Metozel CM® 9.7 mg3

Sodium-SMS 2.0 mg4

Talc 20.0 mg

Magnesium stearate 2.0 mg

Note: 1.

Composed of 75% lactose and 25% microcrystalline cellulose, commercially on the have company Meggle GmbH of Wasserburg, Germany.

2. The hypromellose USP type 2208; 4000 MPa·sec, commercially supplied by the company use of West Point, Pennsylvania.

3. The hypromellose USP type 2208; 15000 MPa·sec, commercially supplied by the company use of West Point, Pennsylvania.

4. Medium viscosity.

Experimental method

Tablets (250 mg)containing 5 mg (2%) bromocriptine, received and tested in accordance with methods described below. The song was received with 75.7% of Cellactose® as directly compressible filler, 8.8% of Methocel CM®, 3.9% Methocel CM® and 0.8% sodium CMC as swellable polymers that control the release, 8% talc as anticlimaxes substances and 0.8% of magnesium stearate as a lubricant.

Drug and all the fillers, in addition to lubrication, sift together the geometric principle manually using a sieve, then mixed with the turbula mixer for 10 minutes After addition of magnesium stearate and the mixture was mixed for another 5 minutes For pressing used rotary 8-local laboratory press with automatic feed of the powder container and devices (12×5 mm).

Testing tablets

Used standard pharmaceutical testing methods and equipment to determine the following:

Hardness: the average value of 16.4 kp (Schleuniger 4M)

Friability: 0,02

The dissolution test according to USP XXIII, R, device 2, 500 ml of 0.01 N. Hcl, 50 rotations/min:



Time (hours)
% Release α-dihydroergocryptine (M +/- SD)
0/521,8+/-3,2
132,5+/-4,4
247,0+/-7,4
465,6+/-7,4
677,8+/-8,1
890,0+/-6,9

Conventional tabletting composition of bromocriptine 2.5 mg, had the following composition: bromkriptin 2.5 mg, lactose 115.5 mg polyvinylpyrrolidone 4 mg, maleic acid 2 mg, magnesium stearate 1.3 mg, colloidal silica 0.35 mg and corn starch 14 mg of the dissolution Study was performed under the same conditions as for the composition of prolonged action of the present invention described in this example, and as a result received a 96.9+/-4,8% release bromocriptine after 0.5 hour.

An example of comparison of the bioavailability of the compositions of the prolonged action of the present invention with the bioavailability of conventional compositions

EXAMPLE 8

Comparative clinical test

The purpose of the study is to assess in healthy volunteers pharmacokinetic characteristics and bioavailability α-dihydroergocryptine in the form of oral pills prolongiro the data according to this invention, described in examples 5 and 6, in comparison with conventional tablets according to the conventional tablet composition described in example 5. The project study is a large-scale, cross, 3 cyclofem study. Twelve volunteers, men were randomly assigned to one of three treatment regimens, separated by a one-week period laundering. The drug is administered orally in a single dose, 10 mg, in the morning on an empty stomach (hungry state was maintained for 4 hours after taking the medicine). Blood samples were collected through a permanent cannula at certain time points up to 72 hours after injection of the drug.

Plasma concentrations during the observation period is shown in the drawing. The results of pharmacokinetic analysis plasmonic concentrations are presented in table A (expressed as average values).

Table And

 The composition of the regular release (from example 5)The composition is prolonged. the term of this invention (example 5)The composition of prolongers. the term of this invention (example 6)
Withmax(NG/ML)147,065,158,2
TIGMASS.(H)1,3 4,68,0
T1/2 eliminat. (h)14,827,942,8
AUCtotal(ng h/ml)865,11107,01894,5

The presented data clearly show that both compositions prolonged action significantly reduces the maximum concentration and slow down the appearance of the peak concentration, especially the composition of prolonged action, described in example 6. The figures presented reflect the low absorption rate and a dramatic reduction of surge absorption, which usually occurs after the introduction of conventional composition.

Three-fold increase in half-life observed for compositions with prolonged action, described in example 6, the indicator prolonged process of absorption compared with the conventional tablet. The bioavailability of the compositions of the prolonged action of the present invention, measured by AUC, were unexpectedly higher than the bioavailability obtained with the conventional tablet.

The foregoing is illustrative of this invention and should not be construed as a limitation. The invention defined by the following claims by equivalent items included in it.

Appendix 1

The dissolution tests in vitro

A. Composition t is adicionou tablet composition

α-Dihydroergocryptine mesilate 20.0 mg

Lactose 148,0 mg

Microcrystalline cellulose 70.0 mg

Crosscarmellose 6.0 mg

Magnesium stearate 4.0 mg

Polyvinylpyrrolidone 2.0 mg

C. the composition of the slow release tablets of the present invention

α-Dihydroergocryptine mesilate20.0 mg4,0%
1Cellactose®368,6 mg73,72%
2Metozel CM®to 44.0 mg8,8%
3Metozel CM®to 19.4 mg3,88%
4Carboxymethylcellulose sodium 7-HXF4.0 mg0,8%
Magnesium stearate Ph. Eur.4.0 mg0,8%
Talc Ph. Eur.40,0 mg8,0%
1Containing 75% lactose and 25% microcrystalline cellulose, commercially supplied by the company Meggle Wasserburg GmbH from Germany.

2The hypromellose USP type 2208; 4000 MPSC, commercially supplied by the firm use of the West Point, Pennsylvania.

3The hypromellose USP type 2208; 15000 MPSC, commercially supplied by the firm use of the West Point, Pennsylvania.

4Medium viscous the ti

Experimental method

The composition was processed by mixing in a mixer with cubic drum (300 liters) for 15 min, 73,72% Cellactose® as directly compressible agent, 8.8% of Methocel CM® and 3,88% Methocel CM® and 0.8% carboxymethylcellulose sodium as swelling agents, control release, 4% α-dihydroergocryptine nelfinavir as the active ingredient and 8% of talc as a filler. After adding 0.8% of magnesium stearate and the mixture was mixed for 15 minutes and the Mixture was extruded using a rotary teletrauma machine (Ronchi 23N), equipped with a capsule puncture (punctions) ⊘12 mm

Testing tablets

Used standard pharmaceutical testing methods and equipment to determine the following:

Hardness: 7,5 Cu (Schleuniger 4M)

Friability: of 0.081%

Average weight: 500 mg

Thickness: 5 mm

C. the composition of the slow release tablets by Zueger (109/7)

α-Dihydroergocryptine mesilate20.0 mg5,0%
Lactose FU176,0 mg44,0%
1Aerosil 2002.0 mg0,5%
2Preziral AT (glycerylmonostearate)20.0 mg5,0
3Metozel EM Premium180,0 mg45,0%
Magnesium stearate2.0 mg0,5%
1Consists of silicon dioxide, commercially supplied by the company Giusto Favarelli SpA, Italy.

2Glycerylmonostearate, commercially supplied by the company Giusto Favarelli SpA, Italy.

3The hypromellose USP type 2208; 4000 MPSC, commercially supplied by the firm use of the West Point, Pennsylvania.

Experimental method

The initial mixture consisting of 5% α-dihydroergocryptine nelfinavir as the active ingredient, 44% lactose and 0.5% Aerosil as fillers, sifted through a sieve. To this mixture was added 45% of Methocel AM Premium and 5% Preciosa AT and mixed for 10 minutes After addition of 0.5% magnesium stearate and the mixture was stirred for 15 min. the Mixture was then encapsulated using manual encapsulating machine.

D. Composition of slow release tablets by Zueger (109/8)

α-Dihydroergocryptine mesilate20.0 mg5,0%
Lactose FU56,0 mg14,0%
1Aerosil 2002.0 mg0,5%
Ȁ 2Preziral AT05 (glycerylmonostearate)200.0 mg50,0%
3Metozel EM Premium120,0 mg30,0%
Magnesium stearate2.0 mg0,5%
1Consists of silicon dioxide, commercially supplied by the company Giusto Favarelli SpA, Italy.

2Glycerylmonostearate, commercially supplied by the company Giusto Favarelli SpA, Italy.

3The hypromellose USP type 2208; 4000 MPa·sec, commercially supplied by the firm use of the West Point, Pennsylvania.

Experimental method

The initial mixture consisting of 5% α-dihydroergocryptine nelfinavir as the active ingredient, 14% lactose and 0.5% Aerosil as fillers, sifted through a sieve. To this mixture was added 30% Methocel AM Premium and 50% of Preciosa AT and mixed for 10 minutes After addition of 0.5% magnesium stearate and the mixture was stirred for 15 min. the Mixture was then encapsulated using manual encapsulating machine.

That is, the Results of dissolution tests in vitro

The dissolution tests were performed in accordance with USP XXIII, str, device 2, 500 ml of 0.01 N. Hcl, 50 rpm

Table 1.

Traditional tablet composition
Time (hours)% released α-dihydroergocryptine
After 0.596,52%

Table 2.

Prolonged release α-dihydroergocryptine according to the present invention
Time (hours)% released α-dihydroergocryptine
122,6%
448,0%
880.2%of
Table 3.

Prolonged release α-dihydroergocryptine by Zueger (109/7)
Time (hours)% released α-dihydroergocryptine
120,2%
231,8%
448,1%
658,0%
868,6%
2094,2%
Table 4.

Prolonged release α-dihydroergocryptine by Zueger (109/8)
Time (hours)% released α-dihydroergocryptine
114,6%
225,5%
439,3%
6/td> 48,6%
859,1%
2088,4%

Annex 2

Comparative clinical test

Purpose

The purpose of the study is to assess the pharmacokinetic characteristics and bioavailability α-dihydroergocryptine in the form of oral prolonged release tablets according to this invention, which are described in Annex 1 (hereinafter called “B”), compared to: conventional tablets with traditional tablets composition described in Annex 1 (hereinafter called “A”), prolonged release capsules, prepared in accordance with the method described Zueger (U.S. patent No. 5069911), described in Annex 1 as 109/7 (hereinafter referred to as “C”), and prolonged release capsules prepared in accordance with the method described Zueger (U.S. patent No. 5069911), described in Annex 1 as 109/8 (hereinafter referred to as “D”).

The research was conducted in two phases. In the first phase, pharmacokinetic properties “a” and “b” were studied in an open, cross -, 2-cyclofem study. Twelve volunteers-men were randomly assigned to one of two treatment regimens, separated by a one-week period laundering. The drug is administered orally in a dose of 20 mg in the morning on an empty stomach. Blood samples from Irali through a permanent cannula at certain time points up to 72 hours after injection of the drug.

Plasma concentrations during the observation period is shown in the drawing. The results of pharmacokinetic analysis of concentrations in plasma are presented in table 6 (expressed as average values).

Table 6

Pharmacokinetic analysis of the composition of the regular release and prolonged release composition according to this invention
 “And” Composition normal release“In” prolonged release Composition according to this invention
Withmax(ng/ml)397,0153,4
Tmax(h)0,86,9
AUC0→t576,22006,0
(ng·h/ml)  

In the second phase pharmacokinetic properties “A”, “C” and “D” were studied in an open, cross, 3-cyclofem study. Six volunteers-men were randomly assigned to one of three treatment regimens, separated by a one-week period laundering. The drug is administered orally in a dose of 20 mg in the morning on an empty stomach. Blood samples were collected through a permanent cannula at certain time points, vplo the ü up to 72 hours after injection of the drug.

The results of pharmacokinetic analysis of concentrations in plasma are presented in table 7 (expressed as average values).

Table 7

Pharmacokinetic analysis of the composition of the regular release and prolonged release composition by Zueger
 “And” Composition normal releaseIn” Composition sustained release 109/7“With” Composition sustained release 109/8
Withmax(ng/ml)397,0153,4153,4
Tmax(H)0,86,96,9
AUC0→t(ng·h/ml)576,22006,02006,0

The data presented clearly show that all the songs are extended release, namely “b”, “C” and “D”greatly reduces the maximum concentration and slow down the appearance of the peak concentration. The data presented reflect the low absorption rate and a strong decline in growth that usually occurs after the introduction of conventional composition.

The bioavailability of the compositions prolonged release “C” and “D”, prepared in accordance with the way the m described Zueger (U.S. patent No. 5069911), measured by AUC, similar or slightly lower than that of conventional tablets.

In contrast, the bioavailability of the compositions of the prolonged action of the present invention, measured by AUC, is unexpectedly higher than that of conventional tablets.

1. Method for improving bioavailability of ergot derivatives entered using delivery systems with slow release, providing for the consolidation of ergot derivative, or mixtures thereof with pharmaceutically acceptable hydrophilic swellable substance or mixture and one or more pharmaceutically acceptable fillers, where ergot derivative has the formula

in which R1means hydrogen or halogen;

R2means hydrogen or C1-C4alkyl;

R3means isopropyl, sec-butyl, isobutyl or benzyl;

R4means methyl, ethyl or isopropyl, and either

R5means hydrogen and

R6means hydrogen or methoxy, or

R5and R6together correspond to additional communication

moreover, this method is characterized by a specified derivative of ergot to the specified hydrophilic swellable substance is from 1:0.5 to 1:10.

2. The method according to claim 1, in which the hydrophilic swellable substance selected from the group consisting of methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohols, polyoxyethyleneglycol and poloxamers and mixtures thereof.

3. The method according to claim 1, in which one or more pharmaceutically acceptable excipients selected from the group consisting of lubricants, suspendida substances, binders, diluents, flavoring agents, coloring agents, dispersing agents and wetting agents.

4. The method according to any one of claims 1 to 3, wherein the specified derivative of ergot to the specified one or more pharmaceutically acceptable fillers is from 1:3 to 1:100, preferably from 1:5 to 1:80, even more preferably from 1:10 to 1:50.

5. The method according to any one of claims 1 to 4, wherein the derivative of ergot is a α-dihydroergocryptine.

6. The method according to claim 5, wherein the ratio of α-dihydroergocryptine hydrophilic swellable substance is from about 1:0.5 to 1:5, preferably from 1:1 to 1:4.

7. The method according to claim 6, wherein the hydrophilic swellable substance is a hypromellose.

8. The method according to any one of claims 1 to 7, which unite about 5 to 80 mg ergot derivative.

9. Pharmaceutical composition with slow release, containing α-dihydroergocryptine; in pharmaceutical preparations is automatic acceptable swellable substance or mixture and one or more pharmaceutically acceptable excipients; moreover, this composition is characterized by respect α-dihydroergocryptine to the specified swelling substance is from 1:0.5 to 1:5.

10. The composition according to claim 9, in which the pharmaceutically acceptable swellable substance is a hydrophilic swelling agent.

11. The composition according to claim 9, in which the ratio of α-dihydroergocryptine to the specified swelling substance is from about 1:1 to 1:4.

12. Composition according to any one of p-11, in which the hydrophilic swellable substance selected from the group consisting of methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohols, polyoxyethyleneglycol and poloxamers and mixtures thereof.

13. Composition according to any one of p-11, in which one or more pharmaceutically acceptable excipients selected from the group consisting of lubricants, suspendida substances, binders, diluents, flavoring agents, coloring agents, dispersing agents and wetting agents.

14. Composition according to any one OF PP-13, in which the ratio of α-dihydroergocryptine to the specified one or more pharmaceutically acceptable fillers is from about 1:10 to 1:50.

15. The composition according to 14, in which the hydrophilic swellable substance is a hypromellose.

16. Composition according to any one of the 9-15, which unite about 5 to 80 mg ergot derivative.



 

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