BG99078A - Preparation having controllable release - Google Patents

Abstract

The preparation is used for the treatment of moderate and strong pains and is administered orally. It has controlled release, i.e. the medicine is slowly released for a continuous period of time - at least 12 hours and in this way its time of operation is increased. The preparation is based on tramadol or its pharmaceutically applicable salt as active ingredient from 50 to 800 mg, calculated as tramadol hydrochloride.

Description

The present invention relates to a controlled release formulation, a method for the manufacture of MY and its medical use. In particular, the invention relates to a controlled release formulation comprising tramadol or a pharmaceutically acceptable salt thereof.

Tremadol, Which Has the Chemical Name (1) -trans-2 - / (dimethylamino) methyl / -1- (3-methoxyphenyl) cyclohexanol, is an orally active opioid analogue. For many years commercial preparations are for sale Conventional release form of capsules, drops and suppositories containing tramadol and in particular its hydrochloride salt used for treatment of moderate to severe pain. However, these drugs do not provide for the controlled release of tramadol. THERE IS ANYTHING FEAT, NO MORE THAN ANY OVERALLY ENVIRGED, WHAT, WHEN, LONGER, USE, NO, NO, NO, NO, NO, NO, NO, NO, IN THE LITERATED, NO.

It is an object of the present invention to provide a TRAMADOLE CONTROLLED EXPOSURE FOR ORAL APPLICATION SUITABLE FOR AT LEAST TWELVE HOURS (EXAMPLE UP TO 24 HOURS).

The present invention provides a controlled-release preparation containing tramadol or a pharmaceutically acceptable oral salt thereof.

2.

PHARMACALLY APPLICABLE PHARMACEUTICALLY APPLICABLE APPLICABLE SALVATED Salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, borons, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, salts, valves, PRIMARY HYDROCHLORIDE SALT is preferred.

Kontrolirdno osvo6oZhdavane preparation according to the invention is this preparation that allows slow release of the drug over an extended period of time, thus increasing the duration of the drug as compared to that achieved in the usual release. A PREPARED PREPARATION OF THESE KINDS SUPPORTS THE CONCENTRATION OF THE MEDICINE IN THE BLOOD IN THE THERAPEUTIC EFFECT FOR 12 OR MORE HOURS.

The present invention has been found to be yes

NOW, NOW, NO

· »** '

TABLE 1 RPFME (H) % TRAMADOG FREE 1 0-50 2 0-75 4 3-95 8 10-100 12 20-100 16 30-100 24 50-100 36 > 80

3.

Another preferred preparation especially suitable for

DOSAGE TWO TIMES A DAY, IT IS A RELEASE OF RELEASE IN ACCORDANCE WITH THE FOLLOWING 7o VALID OF TRAMADOL:

TABLE 2 TIME (H) % TRAMADOG FREE 1 20-50 2 40-75 4 60-95 8 80-100 12 90-100

Another preferred preparation especially suitable for

DOSAGE ONE ADMINISTRATION DAILY, RELEASE RELEASE

IN VITRO MEETING THE FOLLOWING% TRAMADOL LEVEL VALUE:

TABLE 3 TIME- (H) % TRAMADOG FREE 1 0-50 2 0-75 4 10-95 8 35-100 12 55-100 16 70-100 24 > 90

4.

Another preferred preparation according to

THE INVENTION IS ALSO A PARTICULARLY FITTING DOSAGE

ON DAY, HAS A RELEASE OF RELEASE IN VITRO COMPLIANT

THE FOLLOWING% TRAMADOL LEVEL VALUE:

TABLE TIME (H) % Tramadol is released 1 O-ZO 2 0-40 4 3-55 8 10-65 12 20-75 16 30-88 24 50-100 36 > 80

Πθ-PREFERRED DOSAGE PREPARATION ONE ADMINISTRATION

DAILY TO HAVE A LEVEL OF RELEASE IN VITRO IN EFFECT:

TABLE 5 TIME (H) % Tramadol is released 1 10-30 2 17-37 4 27-47 8 40-60 12 49-69 16 57-77

5.

Another preferred dissolution rate in vitro RESULT release controlled release formulation, appointment twice a day, according to the invention is between 5 and 50% (by weight) released TRAMADOL after 1 hour, between 10 and 75% (by weight) released TRAMADOL AFTER 2 HOURS BETWEEN 20 AND 95 (WEIGHTED) Tramadol is released AFTER 4 HOURS, BETWEEN 40 and 100% (WEIGHTY) is released TRAMADOLE AFTER 8 HOURS, OVER 8% Tramadol released after 18 hours and more than 80% (by weight) Tramadol released after 24 O'CLOCK.

In addition, in the case of a controlled release preparation of two times a day, it is preferable after 8 hours of oral administration to be absorbed in VITRO between 70 and 95% (weights), 77% AFTER 12 HOURS - BETWEEN 80 AND 100% (WEIGHTED) Tramadol.

A preparation according to the invention suitable for twice daily dosing may have τ _μδυ 1.5 to 8 HOURS, # * - ·. FIG

2 TO 7 HOURS AND W ₅ Q VALUE IN DISTANCE 10 TO

O'CLOCK.

The parameter W ₅ q determines the width of the nl plasma PROFILE at 50% with _MAX , TE. THE TIME AT WHICH Plasma CONCENTRATIONS ARE EQUAL OR MORE THAN 50% OF THE HIGHER CONCENTRATION. The parameter is determined by linear interpolation ΗΛ LABORATED DATA and reflects RLLLLTL during the time between the FIRST (OR ONLY) NLRSTAK and the LATEST (OR EASY).

Said in vitro release values

THESE ARE RECEIVED THROUGH PH PHASE MEASUREMENTS.

6.

(EXCEPT THERE IS NOTHING MENTIONED OTHERWISE) ON SUN / MINW 900 ML

0.1 N HYDROCHLORIC ACID AT 37 ° C USING UV DETECTION AT 270

Controlled preparation osvo6oZhdavane according to the invention preferably contains an analgesically effective amount of tramadol or pharmaceutically acceptable salt thereof, usually in the range of 50 to 800 MG IN PARTICULAR 100,200,300, 400 TO 600 MG (glyphosate TRAMADOL hydrochloride Rid) of edinichΗΛ DOSE.

The preparation of kontrolirlno osvo6oZhdavane invention can be prepared for example as granules, spheroids, tlblEtki, microencapsulated forms, klpsuli, suspensions with controlled "release or in vsyakd Other suitable dosage form, vklyuchvlshtA tlkivA granules, spheroids, tlblEtki etc.

DICTIVE INGREDIENT IN THE PREPARATION ACCORDING TO THE INVENTION FOR CONVENIENCE MAY BE INSTALLED IN THE MATRIX. This can be any matrix, allowing controlled release of tramadol for at least twelve hours period, preferably This should permit the rate of dissolution and absorption of tramadol IN VITRO within the range defined GORE.PREDPOCHITA matrix BE CONTROLLED RELEASE. IN THE ALTERNATIVE IMPLEMENTATION OF THE INVENTION MAY BE USED NORMAL RELEASE MATRIX BUT WITH A COVERED LAYER PROVIDING CONTROLLING

Suitable materials for inclusion in dies are CONTROLLED RELEASE:

l / hydrophilic or hydrophobic POLYMERS such as TIRES, cellulose ethers, dcryl resins and protein derivatives. Of all these polymers, cellulose ethers and more particularly alkyl cellulose are preferred. The preparation is usually comprised between 1% and 8% (by weight) of one or more hydrophilic or hydrophobic polymers.

b / digestible, DALGOZVENNI (Cg- C, especially-12 ^C 40 substituted or unsubstituted hydrocarbons such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes. HYDROCARBONS HAVING TOChkd MELTING between 25 and 90 ° C ARE PREFERRED OUT OF THESE LONG-TERM HYDROCARBON MATERIALS OIL ALCOHOLS ARE PREVIOUSLY PREPARED.

c. The preparation is suitable to contain up to 60% (by weight) of ONE or MORE glycosides.

A particularly suitable control-release matrix including one or more dcyclic celluloses and one or more aliphatic alcohols. ALKYCELLULOSE IS PREFERRED

Cj-Οβ ALKYLCELLULOSE AND MORE SPECIAL ETHYL CELLULOSE. CONTROLLED-RELEASE PREPARATION According to the invention, it is suitable to contain from 5 to 30% (by weight) aliphatic alcohol, more than 10% by weight.

Optionally, a controlled release matrix may also contain other pharmaceutical SUITABLE ingredients that are common for pharmacy as diluent, bdLSAMI, binders, granulating aids, colorants, flavorings, surfactants, regulators, PROTIVO8.

Adhesives and glidants, for example dibutyl ointments, ammonium hydroxide, oleic acid and colloidal silica.

The control release preparation according to the invention can be coated with the usual ¹ film coating materials used in Pharmacy. It is preferable to use a water film coating.

IN AN ALTERNATIVE EMBODIMENT, THE CONTROLLED-RELEASE PREPARATION ACCORDING TO THE INVENTION MAY INCLUDE A NORMALLY RELEASE MATERIAL PREFERREDLY THE PREPARATION INCLUDES A NORMAL RELEASE MATRIX WITH A CONTROLLED RELEASE COVER. Preferably, the formulation includes film-coated Feroids containing the Active Ingredient and a substance for the preparation of the Feroid Form (Feronizing Agent),

SPHERONIZING AGENT CAN BE ANY PHARMACEUTICAL

SUITABLE MATERIAL THAT MAY BE SHAPED SPEROIDLY TOGETHER WITH THE ACTIVE INGREDIENT. A preferred ferronising agent is microcrystalline cellulose. For example, the microcrystalline cellulose AVICEL PH 101 or AVICEL PH-102 is suitable for use.

Optionally, spheroids may also contain other Pharmaceutically Applicable Ingredients commonly used in the Pharmaceutical Field, and NON-BINDING SUBSTANCES. Suitable binders include water soluble polymers VOZORAZTVORIMI hydroxyalkylcellulose (EG HIDROHSIPROPILTSELULOZA) OR water-insoluble polymers (also tlkd CAN CONTRIBUTE TO DELIVER THE PROPERTIES

9.

CONTROLLED RELEASE RELATED TO ACRYLPOLYMERS OR COPOLYMERS, FOR example ETHYL CELLULOSE. SUITABLE VOLUME SUBSTANCES ARE LOSSES THAT INCLUDE.

THE SPEROIDS ARE COVERED WITH MATERIAL. WHICH ALLOWS THE RELEASE OF THE ACTIVE INGREDIENT WITH CONTROLLED SPEED IN THE WATER ENVIRONMENT. Suitable roofing materials with controlled release are those that include water-insoluble waxes and polymers such as polymethacrylates (eg Eudragit POLYMERS, MARKETS)

In the case of an alternative embodiment, the PHARMACEUTICAL MAY BE APPLIED 'AS A ROOFING LAYER ON A SINGLE INERT PLEASE AND THEREFORE COATED WITH A MATERIAL, PROVIDING A CIRCUIT.

In another aspect the present invention provides a method for preparing a controlled release formulation of the invention held in INCORPORATION OF TRAMADOL OR pharmaceutically acceptable salt thereof in a controlled release matrix, for example by:

A / GRANULATION OF A MIXTURE CONTAINING TRAMADOL OR PHARMACEUTICALALLY APPLICABLE TO ITS SALT AND ONE OR MORE ALKYCELLULOSE;

b / MIXTURE ΗΛ DLCYCELLULOSE CONTAINING PELLETS

WITH ONE OR MORE THAN <RTI ID = 0.0> C3-3 </RTI> ALIPHATE ALCOHOL; AND OPTIONAL

B / PELLING AND COVERING

IM WITH A FILM ί IF THIS IS WANTED) OR

D / granulation of the mixture SDADARZHDSHTA tramadol or a pharmaceutically acceptable salt thereof, LAktozd and one or more ALkITsELULOZA with one or more C ₁₂ -36 U ^{LLI LTEN} alcohol and

10.

choice,

E / SHAPING AND PRESSING THE PELLETS AND COVERING THEM WITH A FILM, IF SUCH.

The controlled release preparation according to the INVENTION MAY ALSO BE PREPARED IN THE form of FILM-coated spheroids through:

A / GRANULATION OF A MIXTURE CONTAINING TRAMADOL OR PHARMACEUTICALALLY APPLICABLE HIS SALF ISPHERONIZING AGENT;

b / Extruded granulated mixture to obtain extruded material;

C / SPHERONIZATION OF EXTRUDED MATERIAL BEFORE THE FORMATION OF SPHEROIDS; And

D / COVERAGE OF SPHEROIDS WITH A ROOF FILM.

One preferred form of unit dose in accordance with IZObREETNIETO IS-filled capsules C of controlled release particles essentially comprising the active ingredients, a hydrophobic fusible carrier or diluent and IN. · * · ^W selection - hydrophilic releasable modifier. IN PARTICULAR, controlled release particles is preferably made by a process including the development a mixture of dry active ingredient and controls the material with fusible release, which was then machined in a high speed mixer with input energy sufficient for melting or softening of the fusible MATERIAL BEFORE SHAPING ITS PARTICULARS WITH THE ACTIVE INGREDIENT. After cooling, the resulting particles are screened to produce particles with a size in the range of 0.1 to 3.0 mm, preferably 0.25 to 2.0 mm. The following is an example according to the INVENTION SUITABLE FOR INDUSTRIAL MANUFACTURE OF DOSAGE UNITS.

11.

• f *

When using tdkdvd TECHNOLOGY It was found that in order to achieve faster desired characteristics of the osvoboZhdlvANE (substantially as set forth in vivo, tdkd and in vitro substantially as set forth was diskutirlno above), the mixture which is subjected to obrlbotkl must contain two essential ingradientl , namely:

A / Tramadol or its salt; AND b / a hydrophobic melt carrier or solvent - optional with

C / A release control component containing water soluble ORGANIC OR INORGANIC MATERIAL.

It has been found that the total amount of tramadol or its pharmaceutically applicable salt in the mixture can vary widely, for example from 10 to 90 wt.

The hydrophobic melt component (b) should be a hydrophobic material such as natural or synthetic wax or oil, for example hydrogenated vegetable oil, hydrogenated castor oil, mikRokRistllEn wax, beeswax, Carnauba wax or glyceryl monostearate, and have an adequate melting point of 35 ° C to 140 ° C, preferably 45 to 110 ° C.

Release component (c) when

WATER SOLUBLE MATERIAL IS PREFERRED TO BE USED, IT IS USUALLY polyethylene glycol, AND USING A SPECIFIC MATERIAL IS USED PHARMACEUTICALALLY MATERIALS OF LACATAL

Another preferred method of manufacturing the preparation According to the invention includes:

l / mechanical blotter ON HIGH-SPEED MIXER

OF TRAMADOL OR PHARMACEUTICAL APPLICABLE SALT IN IT

12.

rlzdrobEnd Form and razdro6en hidroFo6en Reduce carrier or diluent having a melting point of 35 to 140 ° C and optionally a component controlled release include WATER-melt material or a particulate soluble or insoluble organic or inorganic material at a speed and energy supplied. Allowing the media to be melted or softened, or dissolved until the agglomerates are formed;

b / crushing of large agglomerates to produce grains with controlled release and

C / CONTINUATION OF MECHANICAL PROCESSING AS BY

CHOICE MAY BE ADDED A SMALL PERCENTAGE CARRIER OR SOLVENT d / Optional REPEAT STEP (B), IS POSSIBLE

And (b) ONE OR MORE WAYS.

By this method, it is possible to achieve a high yield (over 80%) of particles of the desired size, with the desired release of tramadol or its salt.

The resulting particles may be screened to eliminate those of a larger or smaller size after being molded into the desired dosage units, for example, by encapsulation in hard gelatin capsules containing the required DOSE OF ACTIVE SUBSTANCE. TABLETS.

STAPCLE (A) OF THE PROCESS CAN BE MADE IN HIGH-SPEED MIXERS OF ORDINARY TYPE WITH STANDARD INTERNAL IMPLEMENTATION OF STAINLESS STOMACTL The mixture is blended ο6ρα · 6οτβα to a temperature of about 40 ° C or higher, whilst mixing produces a cohesive (binding) granular structure with the size of a particle size SUCH MATERIAL FOR THE PERFORMANCE DESCRIBED

13.

ffk

Below, it looks like a set of agglomerates that, when cooled below 40 ° C, have structural uniformity and resistance to fracture between the rings. IN THIS STEP OF THE METHOD, THE AGLOMERATES ARE DIFFERENT SIZES, SHAPES AND APPEARANCE.

Preferably, the agglomerates are allowed to cool. The temperature to which they are cooled is of little importance, which can be maintained at a temperature in the range of room temperature to 37 ° C.

Agglomerates are destroyed by any suitable means of grinding the dust of the BIG AGGLOMERATES, so as to obtain a mixture of powder and small particles / preferably with a diameter of less than 2 mm. It is advisable to continue with the use of a Jackson Crockatt granulator with appropriately sized mesh openings or Comil with an appropriately sized grid. It has been found that in these devices, the LAMP C is used. The too small dimensions of the DUPkATD, the agglomerates that melt under the action of the LADDER or the BURKKAT are obstructed by the restriction. A size 12 sieve has been found to be most suitable.

The sorted material is returned to the high-speed mixer and the process continues. This is thought to result in the adhesion of finer particles into particles of the same size range.

In a preferred embodiment of the inventive method processing of sorting MATERIAL USED continued until the hydrophobic fusible MATERIALS START to soften (melt), and then optionally added ADDITIONAL

14.

HYDROPHOBIC STOPPING MATERIAL. Stirring is continued until the mixture is transformed into particle sizes of the desired size in a predefined range.

TO ENSURE THE EQUIPMENT OF THE INGREDIENTS IN THE HIGH-SPEED MIXER, AT LEAST IT IS PREFERRED TO AT LEAST SOME OF THE ENERGY TO BE SUPPLIED FROM THE MICROWAVE ENERGY SOURCES.

Energy can also be supplied by other sources such as the heating jacket or through the mixer mixer and the blade blades.

Once the particles are formed, they are cooled or left to cool and after that they can be sifted to remove those from them that are larger or smaller.

The particles obtained can be used for the preparation of dosage units in accordance with the invention, such as tablets or capsules, for the well-known ones.

It was also found that particles. containing Tramadol or its salt produced by the method of melting, as described in the PCT Application / CE 93/00225 and the method described and pretending to be our previous non-publ THE METHOD DESCRIBED HERE ARE PARTICULARLY SUITABLE FOR THE TREATMENT OF PARTICLES IN THE FORM OF TABLETS.

It has been found that by appropriate sorting of the materials used in Particle Formation and the preparation of TABLETS. as well as the proportions in which they are used, it enables a considerable degree of control to be achieved on the maximum solubility values and the release of tramadol or its salt from the compressed oil.

15.

Usually to form a tablet in accordance with the invention particles prepared substantially as set forth 6eshe described above impurities tableting excipients for example, one or more of the standard excipients such as diluents, lubricants, binders, flowing excipients, disintegrating agents, SURFACE ACTIVE SUBSTANCES OR WATER-SOLUBLE POLYMER MATERIALS.

Suitable diluents are, for example, microcrystalline cellulose, lacto03; and also two-calcium phosphate. Suitable lubricants are, for example, magnesium stearate and sodium stearyl fumarate. SUITABLE BINDING AGENTS are, for example, HYDROXYPROPYLPYLMETHYL CELLULOSE, POLYVIDONE and METHYL CELLULOSE.

Suitable disintegrating agents are starch, sodium glycogen glycolate, croscopyodium sodium and croscarmalose.

SUITABLE SURFACES The active ingredients are POLOXAMER 188, polysorbate 80, and sodium lauryl sulfate.

SUITABLE AUXILIARY ASSISTANTS ARE SOAL, Colloidal Anhydrous Quartz.

SUITABLE WATER SOLUBLE POLYMERS ARE PE6 WITH MOLECULAR WEIGHT IN A RANGE OF 1000 TO 6000.

To produce tablets of the invention, particles can be stirred or blended with the desired excipient (if any) using conventional procedures as using U-kOHYC OF TROShAkA or mixing bunker. The resulting mixture can be refinished according to the usual tabletting procedure using a size-appropriate tabletting mold. The TABLETS CAN BE MANUFACTURED BY THE USE OF CONVENTIONAL TABLET MACHINES AS EXAMPLES,

16.

THE FOLLOWING DESCRIPTIONS ARE PROVIDED ON A STANDARD MACHINE F3 WITH ONE POASON OR A RILL 15 PURPOSE MACHINE FOR KILLIAN.

Generally speaking, it was found that even with such HIGHLY WATER active agent as tramadol or salt tab ~ Letcani formed by compression by standard methods give very low values osvoboZhdAvdnE of active ingredient IE CONSIDERING THE RELEASE FOR THE PERIOD BIGGER THAN

2 ...... 24 HOURS, AND MUCH MORE THAN 36 HOURS. IT WAS ESTABLISHED THAT THE RELEASE PROFILE CAN BE ADJUSTED IN MANY WAYS. For example, higher drug values are associated with increasing release rates; USE OF USE OF USE OF USE THROUGH CONTROL OF THE RELATIVE VALUES OF THESE INGREDIENTS, IT IS POSSIBLE TO ACHIEVE A PRELIMINARY PROFILE OF TRIMADOL OR NIAMA OR NIAMA

SOL.

The following examples are given to understand the invention, which are ONLY illustrative:

EXAMPLE 1.

THE TABLETS WERE PREPARED WITH THE FOLLOWING COMPOSITION: MG / TABLETS

Tramadol hydrochloride100

Ph.Eur.68.0

Ethylcellulose (Surelease R 25% solids) 15

Chemical Purified Water Ph.Eur13,3 *

Cetostearyl Alcohol Ph.Eur.42,00 (DEHIDAR Paraffin O)

Magnesium cteapat Ph.Eur2,00

Purified tdlk Ph.Eur.

at pgtrdngnd PP RPP.MF s il pNrlNpttEltl

230,00

17,

TRAMADOL HYDROCHLORIDE (100 MH) AND LACTOSE (68 MH) HAVE BEEN GRANULATED. The granules 6 were then dried at 60 ° C and passed through a sieve with apertures of 1 mm.

HEATED Tramadol containing pellets was added molten cetostearyl alcohol (42 mg) and the whole mixture was stirred very carefully. The pellets were left to cool and were sieved through a sieve with a mesh size of 1.6 mm. THEN THERE WAS ADDED CHEMICAL PURE WATER AND MAGNESIUM STEARATE, WHICH WAS MIXED WITH THE PELLETS. THEREFORE THE PELLETS WERE COMPRESSED IN THE TABLETS.

THE TABLETS WERE COVERED WITH FILM COVER WITH THE FOLLOWING COMPOSITION:

MG / TABLE

HYDROPROPYL METHYL CELLULOSE0,770

Ph.Eur.15.eps. (Methocel E 15)

HYDROXYPRIPOLMETHYL cellulose 3.87

Ph.Eur.5 cps (Methocel E 5)

Obsiraire M-1-7111 B (33% solids) 2.57

Polyethylene glycol 400 USNF0,520

Purified Talc Ph.Eur0,270

Chemical water purified Ph.Eur 55,52 *

X REMOVED DURING TREATMENT

18.

EXAMPLE 2.

THE TABLETS MADE WITH THE FOLLOWING COMPOSITION:

MG / TABLE

Tramadol hydrochloride 100.00 Lactose Ph.Eur 58.00 Ethylcellulose US NF 15.00 (Ethocel 45 CP) CETOSTEARIL ALCOHOL PH.EUR. 52.00 (Dehydag Magnesium stearate Ph.Eur 2.00 Purified TLC Ph.Eur 3.00

A mixture of tramadol hydrochloride (100 mg), ldctose (58 mg) and ethyl cellulose (15 mg) were granulated, while at the same time adding a molten ceto-stearyl alcocholomegnocholomegic acid The granules were then left to cool and sieved through a sieve with an opening size of 1.6 mm. Purified talc and magnesium stearate were added, which were mixed with the pellets. THEREFORE THE PELLETS WERE COMPRESSED IN TABLETS WHICH WERE COATED WITH FILM COATING WITH A COMPOSITION ANALOGICALLY TO THOSE OF EXAMPLE 1.

EXAMPLE 3

Movie Cover Cards were produced on

THE METHOD DESCRIBED IN EXAMPLE 2 WHICH HAS THE FOLLOWING COMPOSITION:

MG / TABLE

100.00 70.00

12.50

Tramadol hydrochloride

Ldctose Ph.Eur.

Hydroxyethyl Cellulose Ph.Eur

19.

Cetostearyl Alcohol Ph.Eur 42.00 Magnesium stearate Ph.Eur 2.00 Purified TLC Ph.Eur 3.00

SOLUTION RESEARCH IN VITRO

In vitro dissolution studies 6 were performed on TABLES prepared as described above.

The results are given in Tblcl 1.

TABLE 1 % By weight of tramadol released Time (n) Example 1 Example 2 * Example 3 1 39 35 43 2 52 47 60 4 67 62 84 8 82 78 97 12 90 86 -

X Measured in the core of the tablet.

In an experiment involving 12 HEALTHY SERUM volunteers

TRAMADOL LEVELS AFTER TAKING ONE TABLE MADE IN ACCORDANCE WITH EXAMPLE 2, IT WAS DETERMINED AS THESE. ILLUSTRATED in Figure 1.

20.

EXAMPLES 4 AND 5

Particles having the compositions given in Table II below were prepared by the following actions:

ι. Placing Ingredients (a) and (c) (Total Weight for Batch 0.7 kg) IN A TANK WITH A 10 L LABEL OF A COLLETE GRAL MIXER, OR ANOTHER MIXER MIXER

WITH MIXING AND GRANULATING VARIABLES OF VARIABLE SPEED.

n. Stirring of ingredients at a speed of 1501000 rpm and simultaneous application of heating to the agglomeration of the contents of the tank.

hi. Sort agglomerated material by COMING IT through COMIL / JAKSON CROCKATT TO GET A GRAIN WITH CONTROLLED RELEASE.

iv. Heating and mixing of the sorted material in the 10 liter COLLETTE GRAL TANK until the same conglomerates are formed with dimensions falling in the pre-set 80% by default. It takes about 5 minutes.

ν. Removing the conglomerlites from the mixer and sieving them through a 0.5 and 2 mm mesh screen to separate the conglomerates of the appropriate size.

TABLE II EXAMPLE 4 5 (a) Tramadol HCI (wt.%) 50 75 (c) Hydrogenated vegetable oil (% by weight) 50 25

21.

EXAMPLE 5

SAMPLES FROM THE PARTICLES OBTAINED IN EXAMPLE 4 WERE MIXED WITH MAGNESIUM STEARATE AND PURE TALK USING A COOKHYCHA CRUSHER OR MIXER BUNK. THE MIXTURE AFTER THIS WAS COMPRESSED WITH THE USE OF (1) 14 X 6 MM, (2) 16 X 7 mm, or (3) 18,6 X 7,5 MM INSTRUMENTAL EQUIPMENT, FOR SHAPING MACHINES 3 OBJECTIVE FOR PREPARATION OF TABLETS CONTAINING 200,300 AND 400 MGR Tramadol HCL SINGLE DOSAGE INGREDIENTS AS FOLLOWS:

TABLE III TABLE MGH / TABLE INGREDIENT 1 2 3 Tramadol HCI 200 300 400 HYDROGENATED VEGETABLE OIL 200 300 400 Intermediate total weight 400 600 800 Purified TLC 12.63 18.95 25.26 Magnesium stearate 8.42 12.63 16.84

THE TABLETS WERE ASSESSED FROM THE DEMONSTRATION POINT OF IMMEDIATE USING PH.EUR. BATTLE METHOD, 100 RPM 01 N HCl.

FOR EVALUATION OF NON-COMPRESSED PARTICLES PH.Eur Blades have been replaced by PH. EUR. NETWORK.

22.

The results are slippery on Tblitzl IV:

TABLE IV Hours after STARTING THE TEST PARTICLES TABLE 1 TABLE2 TABLETKAS % Tramadol HCI is released 1 54 16 15 15 2 68 23 20 21 3 76 28 25 25 4 82 32 28 28 6 89 40 35 35 8 93 46 41 40 10 96 50 45 45 12 98 55 49 49 16 100 63 57 56 20 NR 70 63 NR

These results confirm the effectiveness of the release ckOPOCTTA TABLETTING.

EXAMPLE 7

SAMPLES OF THE PARTICLES OBTAINED IN EXAMPLE 5 WERE TABLETED BY A PROCEDURE SIMILAR TO THOSE OF EXAMPLE 3 AS THE DOSAGE INGREDIENTS AS FOLLOWS:

23.

TABLE V TABLE INGREDIENT MGH / TABLE 4 5 6 Tramadol HCI 200 300 400 HYDROGENATED VEGETABLE OIL 66.7 100 133 Intermediate total weight 266.7 400 533 Purified TLC 7.63 11.44 15.25 Magnesium stearate 5.16 7.63 10.17

TABLETS AND SAMPLES OF NON-COMPRESSIONAL CONGLOMERATES (ALWAYS SAMPLES CONTAINING 400 MGR Tramadol HYDROCHLORIDE) WERE ESTIMATED BY THE DISSOLUTION-DISSOLUTION METHOD. THE RESULTS ARE SHOWN IN TABLE VI:

TABLE VI Hours after start- test Particles TABLE4 TABLET TABLEbook % Tramadol HCI is released 1 77 43 40 * 42 2 92 64 55 56 3 98 75 65 66 4 100 83 72 73 6 102 94 83 84 8 102 100 91 91 10 102 NR 96 97

24.

These results pokdzvAt that by increasing the content of HIGHLY WATER OF TRAMADOL HYDROCHLORIDE (75% w / w in this example compared with 50% w / w in Example 6) can be achieved significantly greater rate of release of active ingredient .

EXAMPLE 8.

Example 4 was repeated, but with the following composition:

Tramadol HCL 200 mg / tablet

HYDROGENATED VEGETABLE OIL 163 MGR / TABLE

The conglomerates obtained were mixed as 6e

DESCRIBED IN EXAMPLE 6 C

Purified tdlk 11.5 mg / tdbl

Magnesium stearate 7.66 mg / dbl

The mixture was then compressed into example 6, but using 15 mm x 6.5 mm normal flat / flat molding dies with recesses for the kdpsulite.

The resultant TLC plates were evaluated by the dissolution method described above.

The results are in the afternoon in Table VII.

In an EXPERIMENT involving five healthy volunteers, the plasma PROFILE RECEIVED AFTER SINGLE TABLET ACCEPT is shown in Figure 2, which is also compared with the intake of 100 Pills in sale.

25.

TABLE VII

HOURS AFTER STARTING. AT TFCTA ^% Tramadol HCI is released 1 20 2 27 3 32 4 37 6 44 8 50 10 55 12 60 16 67 20 73 24 77

26.

Claims (15)

1. Controlled release preparation, characterized by the fact that it contains tramadol or a pharmaceutically acceptable salt for oral administration. 2. A controlled release preparation according to Claim 1, characterized in that it contains from 50 to 800 mg of tramadol (calculated as tramadol hydrochloride). 3. Control release preparation according to claim 1 or 2, characterized in that it has a degree of dissolution in vitro (measured as described herein), as follows: TIME (H) % TRAMADOG FREE 1 O-5O 2 0-75 4 3-95 8 10-100 12 20-100 16 30-100 24 50-100 36 > 80 4. Controlled release preparation according to Claim 1 or 2, characterized by the degree IN SOLUTION IN VITRO AS FOLLOWS: 27. TIME (H) % QCROfionEH Tramadol 1 20-50 2 40-75 4 60-95 8 80-100 12 90-100 5. An Iontrolled Release Preparation as claimed in claim 1 or 2, characterized in that it has a dissolution rate in VITRO (as measured above) as follows: TIME - OP % _D £ FREE Tramadol 1 0-50 2 0-75 4 10-95 8 35-100 12 55-100 16 70-100 24 > 90 28. 6. Controlled release preparation according to Claim 1 or 2, characterized by the fact that it has a dissolution rate in VITRO (as measured above) as follows: TIME (H) % Tramadol released 1 O-ZO 2 0-40 4 3-55 8 10-65 12 20-75 16 30-88 24 50-100 36 > 80 7. A solid oral dosage form with kontrolirdno release according to one of claims 1 to 6, characterized in that it comprises a therapeutically effective amount of tramadol or a salt thereof in a matrix adapted to provide controlled release of tramadol or salt thereof upon oral ACCEPT. 8. A dosage form according to claim 7, characterized in that, the matrix comprises a matrix C controlled release comprising at least one alkyl, Cj PREFERRED TO Cg alkyl, cellulose, at least Cj ₂ TO C ^ g, A PREFERRED C _{1Z |} TO C ₂ 2 'ALIPHATE ALCOHOL AND, optionally, LESS ONE POLYALKYLGLYCOL, PREFERRED POLYETHYLENGLYCOL. 29. A dosage form according to claim 8, characterized in that AT LEAST ONE ALKYCELLULOSE is ETHYCELLULOSE. A dosage form according to claim 8 or 9, characterized in that it includes from 1 to 20% by weight / weight, preferably 2 to 15% by weight / weight, of one or more alkyl celluloses. A dosage form according to one of the claims 8 Up to 10, characterized in that the aliphatic alcohol contains lauryl alcohol, myristyl alcohol, stearyl alcohol OR preferably cetyl alcohol or alcohol. Method according to one of Claims 8 to 11, characterized in that the dosage form contains from 5 to 30% by weight / weight aliphatic alcohol, preferably from 10 to 25% by weight / weight of aliphatic or aliphatic aliphatic. A dosage form according to one of the claims of 1 to 6, in the Form of Spheroids Coated with Film Coating, characterized in that the spheroid matrix includes a spheronizing agent, preferably a microcrystalline. Dosage Form according to one of Claims 1 to 6, in the Form of Conglomerates, characterized in that the matrix contains a hydrophobic top carrier or solvent having a melting point of from 35 to 140 ° C. INCLUDING WATER SOLUBLE MATERIAL OR CRUSHED SOLUBLE OR INSOLVED ORGANIC OR INORGANIC MATERIAL. A dosage form according to any one of claims 1 to 6, characterized in that it contains a tablet formed by compressing the ng conglomerate in accordance with claim 14.