HK1020876B - Tramadol multiple unit formulations - Google Patents
Tramadol multiple unit formulations Download PDFInfo
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- HK1020876B HK1020876B HK99106029.4A HK99106029A HK1020876B HK 1020876 B HK1020876 B HK 1020876B HK 99106029 A HK99106029 A HK 99106029A HK 1020876 B HK1020876 B HK 1020876B
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Description
Technical Field
The invention relates to an oral multi-dosage unit preparation consisting of sustained-release pellets and a preparation method thereof, wherein the sustained-release pellets contain tramadol or a physiologically acceptable salt thereof and at least one pharmaceutically acceptable sustained-release substance.
Background
Tramadol ((1 RS; 2RS) -2- [ (dimethylamino) methyl ] -1- (3-methoxyphenyl) cyclohexanol) is an analgesic effective against both severe and moderate pain.
The commercially available oral sustained release pharmaceutical forms of tramadol are based on tablet dosage formulations and their single dose unit dosage forms suffer from drawbacks not found in multi-dose unit dosage forms. The single-dose units are in the form of individual drugs which, for example, can pass through the gastrointestinal tract without disintegrating (matrix tablets), become smaller with disintegration (erosion tablets) or release the active compound only in the intestinal tract (enteric tablets).
A multiple dosage unit is a pharmaceutical form that, when administered, can be broken down into a number of subunits that are carriers of the character of the pharmaceutical form. In the case of multiple unit sustained release medicaments, there may be significant differences in the gastric residence time of the medicament, which will result in irregular transport of the medicament in the gastrointestinal tract and thus in differences in blood concentration values. Furthermore, multiple dosage unit drug forms are less susceptible to local irritation than single dosage unit drug forms. Also it avoids the risk of "dose dumping", which means that the active compound within the sustained release medicament is released too quickly. (H.Blume, "biopharmaceutical properties of multi-dose unit dosage forms; comparison to single dose units", published by Capsgel, Basel (Switzerland), published by the monograph at Hamburg, 11 months 1988).
The tramadol drug forms specifically described in EP 147780, EP 624366, EP 654263, EP 731694 and DE 4329794 are also such single dose unit drug forms which suffer from the above drawbacks. Pharmaceutical preparations with a slow-release coating are disclosed, for example, in EP 147780, in the form of tablets and granules comprising an inner core of the active compound and a film-coating of polyvinyl alcohol. EP 624366 discloses oral sustained release formulations of tramadol, said formulations preferably being administered in the form of tablets. In particular, the active compound in this case is embedded in a hydrophilic or hydrophobic polymer, a long-chain fatty acid or fatty alcohol and one or more polyethylene glycols of a slow-release matrix.
In addition, film coated spheroids are described. The active compound is embedded in a "globulized" material (e.g. microcrystalline cellulose) and coated with a controlled release film. In EP 731694(WO95/14460) sustained release formulations of opioids, such as pellets, are disclosed which have an analgesic effect at least within 24 hours after oral administration. Micropellets consist of an inner core containing the active compound and coated with a polymer film suitable for sustained release. In addition to the polymer, the film contains, inter alia, acid-soluble compounds and softeners. However, the use of softeners brings about greater disadvantages. The fact that softeners can migrate out of the film is a well-known disadvantage of these substances, which has an influence on the release of the active compound during storage.
Page 2 of EP 147780 states that chemical reactions may also occur between the softening agent and the active compound, which would shorten the half-life of the product. In "pharmaceutical technology" by Sucker, Fuchs, Speiser, Matimer Press, Stuttgart, 1978, it is described that, in addition to the actual membrane-modifying properties, softeners influence the permeability and decomposition of water vapor. The low, but significant, vapor pressure further causes evaporation of the softening agent with concomitant changes in physical properties, such as changes in film dissolution rate.
To date, the micro-pill form of tramadol has not emerged on the market. Pellet formulations differ by their extremely large surface area due to the many, usually hundreds, of subunits present in each therapeutic dose. For easily soluble substances such as tramadol hydrochloride, this may lead to a need for a sustained release material which may significantly reduce the amount of active compound in the pellet formulation in an inappropriate manner. This is particularly undesirable for active compounds that are administered at higher doses, since the required amount of pellets will require the use of larger amounts of hard gelatin capsules. This is unpleasant for the patient and is therefore undesirable in the treatment.
Disclosure of Invention
It is therefore an object of the present invention to provide a multi-unit formulation of tramadol which is particularly easy to accept by the patient and simple to implement, while overcoming the drawbacks of single-dose units and thus ensuring delayed and highly reproducible release.
The invention relates to a multi-dosage unit formulation comprising individual pellets with the same or different degree of delay, said formulation consisting of a starting material coated with tramadol or a physiologically acceptable salt thereof, and this formulation being further coated with at least one mono-or multi-layer film of a pharmaceutically acceptable sustained release substance, which is released from the pellets into the gastrointestinal tract in a delayed manner.
In particular, the invention relates to a multi-dosage unit pharmaceutical formulation containing individual pellets of the same or different degree of sustained release, consisting of starting materials coated with tramadol or a physiologically acceptable salt thereof, coated with a controlled release single-layer film or multilayer film consisting of a substance selected from ethylcellulose having different degrees of ethylation and chain length and/or from shellac and free of a softening agent.
In the pharmaceutical preparations according to the invention, the content of active compound released in delayed form is in the range of 30-85% (preferably 50-75%) by weight, while the content of pharmaceutically acceptable slow-release substances is between 2-40% by weight. The starting material of the sustained-release pellet is sucrose crystals or sugar granules, neutral granules or sugar spheres. The ratio of ethyl cellulose substance to lac substance is preferably 1: 9-9: 1. In the formulations of the invention, tramadol or a physiologically acceptable salt thereof in solution or powder form can be coated on the starting material with a solution of the active compound or a suitable solvent or a suitable binder solution, the solvent being water, a lower alcohol, an alcohol/water mixture or acetone, wherein the lower alcohol is ethanol and isopropanol.
The mechanism controlling the release of the active compound from the pellets can be explained essentially by the following functional principles:
the first possibility is that the sustained release pellet formulation is controlled by an outer membrane;
another way to obtain a suitable sustained release is to have pellets without an outer membrane, but the release of the pellets is accomplished by a controlled release matrix;
finally, a third possibility is to combine the two above-mentioned ways, i.e. matrix controlled release with membrane controlled release to obtain the desired release properties.
Tramadol hydrochloride used in the multi-unit formulations of the invention has superior dissolution characteristics and is utilized to prepare multi-unit formulations according to the invention to form typical film-controlled diffusion pellet formulations.
The pellets in a multi-dosage unit formulation consist of an inner core containing the active compound, which is coated with a single or multiple coating films for controlled release of the active compound. A rapidly disintegrating or rapidly dissolving layer of active compound (initial dose) can be applied to the film using a suitable adhesive, which layer should be suitable for release control after administration.
The active compounds can be processed as such or in the form of mixtures, but the form of mixtures should have a beneficial effect on the processability of the active compounds. For example, mixtures with colloidal silica such as Aerosil 200, sucrose or other suitable materials may be employed.
The pellet core itself consists of an inert internal starting material and the active compound is applied to this starting material in the form of a suitable solution. As starting material for the pellet formulation, for example, sucrose crystals or additional sucrose-corn starch pellets (sugar pellets (Nonpareils), neutral granules, sugar spheres, USP23/NF18) may be used.
Due to the good water solubility of lower alcohols, such as ethanol, isopropanol and alcohol/water mixtures or acetone, the active compounds can be applied to the starting materials in the form of solutions with them as solvents. The above process can be accelerated by the active compound in powder form and in dissolved form or by the use of solvents alone.
In another preferred form of the above preparation step, the active compound in powder form is applied to the starting material with a suitable binder solution. The application of the active compound can be carried out in layers, and after a more or less large amount of application, the application process can be interrupted for a longer or shorter period of time.
Only a sufficient amount of binder solution is used to attach the active compound to the starting material, which binder solution may contain a single binder or a mixture of several binders. The active compound layer thus consists essentially of the active compound itself and only up to 10% or less of one or more binders.
The binder and/or the slow-release substance used may be a polyvinylpyrrolidone such as PVP25, a hydrophilic cellulose ether such as hydroxypropylmethylcellulose, ethylcellulose of varying degrees of ethylation and varying chain lengths, shellac, copolymers corresponding to A, B and methacrylic copolymers of the type C described in USP (United states Pharmacopeia) 23/NF18, having anionic character and based on methacrylic acid and methyl methacrylate or ethyl acrylate such as Eudragit L、Eudragit SAnd Eudragit L100-55Or copolymers of type A and type B with amino methacrylates such as Eudragit RLAnd Eudragit RS) Cellulose acetate phthalate and o-benzeneHydroxypropyl methylcellulose acetate dicarboxylate.
Suitable solvents for the binder and/or the sustained-release substance are preferably water, lower alcohols such as ethanol, isopropanol, alcohol/water mixtures or acetone.
The sustained-release substances may be treated individually or in combination with each other. Preferably, a substance selected from the ethylcellulose series and/or the shellac series is used. For example, a combination of ethyl cellulose and shellac in a ratio of 1: 9 to 9: 1 may be used, and a combination of ethyl cellulose and Eudragit S may be suitably used。
In a particularly preferred embodiment of the invention, a mixture of ethylcellulose and shellac is used as both binder and slow-release substance. By applying or coating the starting material with the active compound using the same polymer as that used for sustained release, tramadol pellets of particularly simple composition can be obtained, which are easy to prepare and contain only a few different adjuvants and are therefore very advantageous for the patient.
Other components of the multi-unit dosage formulations of the present invention may include pharmaceutically acceptable conventional adjuvants, such as mold release agents and flow control agents, such as highly dispersed silicon dioxide, talc and magnesium stearate.
The pellets may optionally have differing degrees of release due to differences in film thickness of the different coating layers or due to the use of different release agents. But also thereby give further possibilities for controlled release of the active compound. In contrast to single-dose unit formulations, the multi-dose unit formulations described above, which contain pellets with the same or different degree of sustained release, can continue through the pylorus, even in the case of pyloric closure, and can be dispersed throughout the gastrointestinal region. This will allow for extremely uniform transport through the gastrointestinal tract.
Pellets were prepared using conventional methods (pharmaceutical granulation technology, edited by isaaghebre-selassie, Marcel Dekker press, new york and basel, 1989).
One preferred preparation method is carried out as follows:
the starting cores are first placed in a coating pan or another suitable apparatus, the active compound or mixture of active compounds is added thereto continuously or in portions, and they are attached to the starting materials with a binder solution. After loading the starting material with the active compound, film coating is carried out with the same or another binder and/or release regulator until the release has reached the desired standard. Pellets containing the active compound which release the active compound in a delayed form can be coated with other active compounds which are only released as initial doses but not in a delayed form by various methods known to the person skilled in the art, for example by sugar coating or solution spraying. In addition to the coating pan, the coating can also be carried out in a fluidized bed.
By drying during and/or after the individual process steps, a reasonable threshold value for the solvent used can be set.
In WO95/14460, a complex process for preparing pellets comprising an ethylcellulose coating and an emollient is disclosed.
In the so-called "curing" process, the pellets are not subjected to conventional post-drying, but are exposed to temperatures and humidities which are technically difficult to achieve, for example, operating at 60 ℃ and a relative air humidity of 80%. In view of such stringent conditions, the above procedure is not applicable to every active compound. Due to the sensitivity of tramadol to moisture, tramadol micropellets will disintegrate under such conditions.
The diameter of the particles of the tramadol pellets is 0.4-3.0mm, preferably 0.6-1.6 mm.
For oral administration, the sustained release of the pellets may optionally be to varying degrees, and the pellets are preferably dispensed into gelatin capsules or compressed into tablets in combination with suitable adjuvants. For patients with difficulty swallowing capsules or tablets, the advantages of dispensing within a capsule are significant, i.e., extremely easy to take. By opening the capsule, the sustained release pellets can be removed and swallowed with a liquid or chyme. In addition, the sustained-release pellet can also be administrated through a stomach or a duodenum.
The amount of active compound released in delayed form in a multi-dose unit formulation is between 30 and 85% by weight, preferably 50 to 75% by weight. The amount of the sustained-release compound in the multi-dosage unit formulation is in the range of 2-40% by weight.
According to the formulation regimen of the present invention, the daily dose required to achieve the desired therapeutic effect may be administered in a single (24-hour formulation) or in two administrations (12-hour formulation). There is no particular limitation on the specific dosage form or specific dosage range. The amount of active compound and the release of active compound may be adapted to all therapeutic needs. Bioavailability testing has demonstrated that all of the biopharmaceutical parameters of sustained release formulations of tramadol meet the needs of subject development after administration of capsule formulations of the invention, e.g., capsules containing 50-200mg tramadol hydrochloride.Release of active Compounds
An in vitro model suitable for the analytical assessment of the release of active compounds should be able to reproduce the physiological pH course of the gastrointestinal tract and should be able to test liquids which reach a slightly basic pH from acidic to slightly acidic. The main criteria for qualitatively assessing the release of active compound in a multi-unit sustained release formulation comprising an active compound with dissolution properties (tramadol hydrochloride) are: adequate sustained release in the acidic pH range was detected, as well as complete release of the active compound, particularly in the weakly acidic to weakly alkaline range, in addition to the expected degree of delay achieved. The only device suitable for the above study is described in the United states Pharmacopeia (USP 23) on pages 1793 to 3012 as "device 3", a more detailed description of such a device is disclosed in the journal of pharmacy, Vol.80 (1991), p.991 and 994.
Detailed Description
The invention is illustrated in more detail by the following examples, which are not intended to limit the subject matter of the invention.Example 1 Preparation of inner cores containing active compounds
With 1150g of a 20% strength ethyl cellulose/shellac (2: 8) solution in an approximately 96% [ v/v ] ethanol/water mixture, 4020g of tramadol hydrochloride/Aerosil mixture was placed in a coating pan to coat 1000g of neutral pellets of appropriate size (e.g., in the range of 0.5-0.6mm diameter). The resulting core was then dried and sieved (0.8-1.4 mm).Coating of films
390g of an 20% strength ethyl cellulose/shellac (2: 8) solution are added to an approximately 96% [ v/v ] ethanol/water mixture and coated over 5.25kg of the active compound-containing core prepared above to coat it with a film. As a mold release agent, 780g of talc was sprayed.Formulation of
| Parts by weight (%) | |
| Tramadol hydrochloride neutral pellet ethyl cellulose shellac Aerosil 200 talc ethanol/water mixture of about 96% (v/v) | 65.516.41.04.00.312.8 proper amount |
The in vitro release of tramadol hydrochloride from the sustained release pellets described in example 1 was determined in apparatus 3, USP23/NF 18. The temperature of the release medium was 37 ℃, the stroke count of the sample tube was 20 strokes/min, and the amount of solution to be tested was 175ml apart for each test.
Starting with a test solution with a pH of 1.5, after a first hour, the sample in the test tube in each case had turned into 175ml of a test solution with a pH of 4.5, after a second hour the pH of the test solution had reached 6.9, after the 4 th hour a new test solution with a pH of 6.9, after the 6 th hour the test solution with a pH of 7.2 and after the 8 th hour the test solution had a pH of 7.5. Spectrophotometric methods were used to determine the amount of active compound released into the solution medium at the above time points. The following release values were measured:
| percentage released in hours |
| 1 342 514 656 758 8412 98 |
Figure 1 illustrates the in vitro release profile of the sustained release pellet of example 1.Example 2
Sustained release pellets of the following formulation were prepared in analogy to example 1:
| parts by weight (%) |
| Tramadol hydrochloride 50.0 neutral pellet 12.2 ethyl cellulose 8.4Eudragit S 0.9Aerosil 2000.2 Talc, 28.3 acetone |
In vitro drug release studies were performed in a manner similar to example 1.
The following release values were measured:
| percentage released in hours |
| 1 302 514 706 818 8812 94 |
Figure 2 illustrates the in vitro release profile of the sustained release pellet of example 2.Example 3
Sustained release pellets of the following formulation were prepared in analogy to example 1:
| parts by weight (%) |
| Tramadol hydrochloride 40.3 neutral pellets 10.1 ethyl cellulose 6.7Aerosil 2000.2 Talc 42.7 about 96% (v/v) ethanol/water mixture |
In vitro drug release studies were performed in a manner similar to example 1.
The following release values were measured:
| percentage released in hours |
| 1 342 594 816 898 9212 93 |
Figure 3 illustrates the in vitro release profile of the sustained release pellet of example 3.Example 4
Sustained release pellets of the following formulation were prepared in analogy to example 1:
| parts by weight (%) |
| Tramadol hydrochloride 59.7 neutral pellets 14.9 Ethyl cellulose 0.7 Lacca 4.7Aerosil 200 0.3 Talc 19.7 ethanol/Water mixture of about 96% (v/v) appropriate amount |
In vitro drug release studies were performed in a manner similar to example 1.
The following release values were measured:
| percentage released in hours |
| 1 352 524 726 848 9512 100 |
Figure 4 illustrates the in vitro release profile of the sustained release pellet of example 4.Example 5
Prepared in analogy to example 1The formula of the sustained-release pellet is as follows:
| parts by weight (%) |
| Tramadol hydrochloride 48.8 neutral pellet 12.2 ethyl cellulose 0.6 shellac 2.3Eudragit S 2.2Aerosil 2000.2 Talc 33.7 about 96% (v/v) ethanol/water mixture |
In vitro drug release studies were performed in a manner similar to example 1.
The following release values were measured:
| percentage released in hours |
| 1 312 584 766 838 8612 89 |
Figure 5 illustrates the in vitro release profile of the sustained release pellet of example 5.Example 6
Sustained release pellets of the following formulation were prepared in analogy to example 1:
| parts by weight (%) |
| Tramadol hydrochloride 64.4 neutral pellet 16.1 Ethyl cellulose 3.5 Lacca 2.3Aerosil 2000.3 Talc 13.4 about 96% (v/v) ethanol/water mixture |
In vitro drug release studies were performed in a manner similar to example 1.
The following release values were measured:
| percentage released in hours |
| 1 392 574 706 788 8412 93 |
Figure 6 illustrates the in vitro release profile of the sustained release pellet of example 6.Example 7
Sustained release pellets of the following formulation were prepared in analogy to example 1:
| parts by weight (%) |
| Tramadol hydrochloride 58.9 neutral pellets 14.8 Ethyl cellulose 0.6 Lacca 4.9Aerosil 2000.3 Talc 20.5 about 96% (v/v) ethanol/water mixture |
In vitro drug release studies were performed in a manner similar to example 1.
The following release values were measured:
| percentage released in hours |
| 1 32 114 476 698 8212 98 |
Figure 7 illustrates the in vitro release profile of the sustained release pellet of example 7.
Claims (18)
1. Multi-dosage unit pharmaceutical formulation comprising individual pellets of the same or different degree of sustained release, said pellets consisting of a starting material coated with tramadol or a physiologically acceptable salt thereof, and being coated with a controlled release single-layer film or multi-layer film, said film consisting of a material selected from ethylcellulose having different degrees of ethylation and chain length and/or from shellac and being free of softeners.
2. Pharmaceutical preparation according to claim 1, characterized in that the content of active compound released in delayed form is in the range of 30-85% by weight, while the content of pharmaceutically acceptable slow-release substances is between 2-40% by weight.
3. Pharmaceutical formulation according to claim 2, characterized in that the content of active compound released in delayed form is in the range of 50-75% by weight.
4. Pharmaceutical preparation according to claim 1, characterized in that the starting material for the sustained-release pellets is sucrose crystals or sugar granules, neutral granules, sugar spheres.
5. Pharmaceutical preparation according to claim 1, characterized in that the ratio of ethyl cellulose to shellac is preferably between 1: 9 and 9: 1.
6. Pharmaceutical formulation according to claim 1, characterized in that tramadol or a physiologically acceptable salt thereof in solution or powder form is coated on the starting material with a solution of the active compound or a suitable solvent or a suitable binder solution.
7. Pharmaceutical preparation according to claim 6, characterized in that the solvent used is water, a lower alcohol, an alcohol/water mixture or acetone.
8. The pharmaceutical formulation according to claim 7, wherein the lower alcohols are ethanol and isopropanol.
9. Pharmaceutical preparation according to claim 6, characterized in that ethylcellulose and/or shellac having different degrees of ethylation and different chain lengths is used as binder.
10. Pharmaceutical formulation according to claims 6-9, characterized in that tramadol or a physiologically acceptable salt thereof is coated on the starting material, preferably in powder form, with a binder solution consisting of ethylcellulose and shellac in an ethanol/water mixture.
11. Pharmaceutical formulation according to claim 1, characterized in that release agents and flow agents may be included as further auxiliaries.
12. Pharmaceutical formulation according to claim 11, characterized in that the auxiliary agent is silicon dioxide, talc or magnesium stearate.
13. Pharmaceutical preparation according to claim 1, characterized in that the particle diameter of the sustained-release pellets is 0.4-3.0 mm.
14. Pharmaceutical preparation according to claim 13, characterized in that the particle diameter of the sustained-release pellets is 0.6-1.6 mm.
15. The pharmaceutical formulation according to claim 1, characterized in that said formulation is in the form of a capsule or a tablet.
16. Pharmaceutical preparation according to claim 15, characterized in that the sustained-release pellets in the capsule are removed and, if necessary, administered separately.
17. The pharmaceutical formulation according to claim 1, characterized in that the formulation is a single use formulation in a 24-hour formulation or a double use formulation in a 12-hour formulation.
18. Process for the preparation of a multiple dose unit formulation according to claim 1, characterized in that the active compound or the mixture of active compounds is applied to the starting material by means of an alcoholic, alcoholic/aqueous or acetonic solution or a binder solution, subsequently treated with a solution consisting of ethylcellulose and/or shellac, optionally with a release agent, to form a suitable film, and the resulting pellets are filled into capsules or compressed into tablets.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19630035.5 | 1996-07-25 | ||
| DE19630035A DE19630035A1 (en) | 1996-07-25 | 1996-07-25 | Tramadol multiple unit formulations |
| PCT/EP1997/003934 WO1998004249A2 (en) | 1996-07-25 | 1997-07-19 | Tramadol multiple unit formulations |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1020876A1 HK1020876A1 (en) | 2000-05-26 |
| HK1020876B true HK1020876B (en) | 2003-10-24 |
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