ES2348157T3 - EXCIPIENT OF MODIFIED RELEASE AND ITS USE. - Google Patents

Abstract

Slow or extended release excipient composition containing a substantially uncrosslinked carboxymethyl starch and a nonionic hydrophilic cellulose ether.

Description

Modified release excipient and its use.

Field of the Invention

The invention relates to a composition of suitable excipient in formulation of a release tablet Slow or extended with an active substance. The invention is also substantially refers to an uncrosslinked SSG for use in such excipient composition

Background of the invention

Polysaccharides and their derivatives are widely used in pharmaceutical formulations and, in different cases, play a fundamental role in determining the level of release from unit dosage. This is desired in cases where the active substances only show a small absorption margin in the gastrointestinal tract or in cases where a pharmaceutical composition has to be released in the body at a constant rate in a desired time scale. . Rahmouni et al . "Characterization of binary mixtures consisting of cross-linked high amylose starch and hydroxypropylmethyl cellulose used in the preparation of controlled release tablets." Binary mixtures consisting of cross-linked high amylose starch and hydroxypropylmethyl cellulose used in the preparation of controlled-release tablets ) Pharm. Dev. Technol. 4 (2003), p. 335-348 mentions that high native crosslinked amylose starch has attracted much attention as a controlled release excipient for the preparation of solid dosage forms. This is attributed to the swelling and gelation properties of the cross-linked starch matrix controlling the diffusion rate of the drugs. The same article also describes that hydroxypropyl methylcellulose (HPMC) is a highly used hydrolytic polymer for the preparation of controlled release tablets. Precisely for that reason, Rahmouni et al . It evaluates the effect of a binary mixture of HPMC and cross-linked starch on the properties of the tablets and the release kinetics of drugs of different solubilities. The results of the study are diverse, but in terms of the level of release it was found that the incorporation of 10% HPMC reduces the release rate of slightly and moderately water-soluble drugs, while the release rate of highly water-soluble drugs was rapid both in the presence as in the absence of HPMC. EP-A-1,382,331 discloses a pharmaceutical formula designed for the controlled release of active substances, where the tablet consists of multiple strata, that is to say a stratum consisting of erodible and / or gellable and / or inflatable hydrophilic polymers and a stratum which contains the active substance to be administered. The first layer acts as a barrier to control the release of the drug, and may include HPMC or carboxymethyl cellulose, among other different polymeric substances. To reach an inflatable stratum EP-A-1,382,331 exemplifies the use of AcDiSol (FMC. Corp. Philadelphia, USA) and Explotab® (Mendel, Carmel, NY, USA), which are commercially available as carboxymethyl cellulose from cross-linked sodium (or croscarmellose sodium) and cross-linked sodium carboxymethyl starch (or sodium starch glycolate) respectively having a moderate swelling potential. WO-A-02/00204 and WO-A-02/070021 provide oral dosage forms for administering antineoplastic agents, where gelation of the vehicle composition for gastric retention retains the antineoplastic drug in the patient's stomach. A superdisintegrant such as cross-linked carboxymethyl cellulose sodium, sodium starch glycolate or cross-linked polyvinyl pyrolidone can be used. Again, the SSG is crosslinked, since it is suggested to use Primojel® or Explotab®. US 6,500,459 describes a pharmaceutical composition for the controlled introduction and sustained release of an active substance, said composition comprising a hydrophilic carrier and a hydrodynamic diffusion intensifier. According to their examples, a mixture of HPMC and Explotab® SSG can be used. WO-A-2004/066981 refers to a pharmaceutical controlled oral release composition comprising metaxalone. It may comprise sodium starch glycolate as commercially available as Explotab® and Primojel®. WO-A-2004/006904 discloses oral dosage forms of controlled release containing acetaminophen. A list of disintegrants is given, among which is Primojel® SSG. Although some of the previous publications do not explicitly mention that the SSG is highly crosslinked, the suggested use of Primojel® or Explotab® inevitably implies that the SSG is highly crosslinked so that it is highly valued in the art. Both Primojel® and Explotab® are used as a reference in the accompanying examples, supporting the invention. WO-A-97/46592 teaches the use of a substantially uncrosslinked carboxymethyl starch as an auxiliary agent to delay drug release. Although steps are taken to prevent cross-linking during etherification of native starch and subsequent drying, the carboxymethyl starch of WO-A-97/46592 nevertheless implies cross-linking to a reasonable degree, due to intermolecular esterification between the fractions of the carboxy of carboxymethyl substituents and the remaining hydroxyl moieties of the carboxymethyl starch. WO-A-97/46592 does not mention the actual level of crosslinking. In addition, the international publication says nothing about the slow-release properties of carboxymethyl starch in combination with other excipients. Outside the scope of slow-release drugs in the form of tablets, cross-linked carboxymethyl starch is well known for its remarkable efficiency in tablet disintegration and improved tablet dissolution, and is often incorporated into tablet formulations where accelerated absorption of water is necessary to disintegrate the tablet as quickly as possible; The function of this type of cross-linked carboxymethyl starch is not to delay drug release.

However, neither the excipients of release provided controlled HPMC or carboxymethyl starch, up to certain cross-linked point, nor the combination of HPMC and starch cross-linked carboxymethyl give a slow release of the drug satisfactory Hence there is a continuing need in the art to continue improving the slow release properties of drugs in the form of tablets through the choice of excipient (s).

Summary of the Invention

An object of the invention is to provide a excipient for speed control that enables better control over the release of the active substance from tablets in comparison with the individual speed control excipients conventional, and without otherwise compromising the properties of the tablet It is especially an objective to provide a excipient for slow or extended release. It has been found now that a combination of carboxymethyl starch and an ether of non-ionic hydrophilic cellulose has a synergistic effect on indices of the release of the active substance, with the condition of that the carboxymethyl starch is substantially uncrosslinked. The surprising effect is highlighted in the accompanying examples by sedimentation measurements, which prove to be directly linked to the release speed of the active substance in an aqueous system. Although you don't want to limit yourself to any theory, corresponds to the inventor's belief that the interaction of cellulose ether with carboxymethyl starch substantially uncrosslinked leads to the formation of a matrix structure of dissolution rate control plus strong which can be obtained using the individual components. The dissolution rate control matrix behaves in Following way. First, water or gastrointestinal fluid hydrates the polymers on the surface of the tablet and the hydrated polymers form an outer layer around the viscous and gelled tablet. This stratum not only contains the polymers but also all other components of the formulation including the active substance. This external stratum meets two Functions: Firstly reduce the speed of water ingress in the center of the tablet, and secondly controls the level in which disperses the active substances from the stratum and Towards the surrounding liquid. The gelled outer layer is dissolves or erodes slowly, but constantly forms a new stratum hydrated and gelled more internally in the compressed. The overall effect is that the tablet dissolves slowly while the hydrated and gelled stratum is moves towards the center of the tablet, and the external strata are dissolve Therefore, improve the dissolution rate of the compressed involves modulation of gel resistance selecting appropriate gelling excipients. In the invention it is essential that the carboxymethyl starch be substantially non crosslinked It has been discovered that release properties slow deteriorate with an increasing degree of crosslinking, put that a high degree of crosslinking in carboxymethyl starch promotes rapid dissolution of real gel instead of release Slowly controlled

Description of the invention

Therefore, the invention relates to a speed control excipient composition containing a substantially uncrosslinked carboxymethyl starch and an ether of nonionic hydrophilic cellulose. The composition allows release slow or extended active substance contained in the formulation of the tablet Although the term "active substance" is predominantly understand by understanding drugs in the sense Pharmacist, also covers nutritious ingredients like vitamins, minerals, proteins, peptides, enzymes, microorganisms, flavorings, etc.

Hydrophilic non-ionic cellulose ether

Initially, the cellulose ether in the excipient composition may be in any form, provided that Be hydrophilic and meet the criteria set out below. In In general, cellulose ether is selected from celluloses of alkyl, hydroxyalkyl celluloses and alkyl celluloses of hydroxyalkyl Cellulose ethers may contain some other substitution by other non-ionic groups, such as acyl groups of esters for example acetate and propionate substituents. Examples of suitable cellulose ethers are methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl ethylcellulose (HPEC), ethylhydroxyethyl cellulose (EHEC), methylcellulose hydroxyethyl (HEMC), and the like. More preferably, the ether of Cellulose is one of those cataloged in the National Pharmacopoeia or most important multinational, such as MC, HEC, CMC or HPMC. By For example, hydroxypropyl methylcellulose appears in the Pharmacopoeia European, United States Pharmacopoeia and Pharmacopoeia Japanese The nature and quantity of substituent groups fixed to the cellulose ether anhydroglucose ring are factors that influence properties such as organic solubility and thermal gelation temperature of aqueous solutions containing the cellulose ether. It is within the scope of Expert knowledge determining the actual degree of substitution and the molecular weight of the appropriate selected cellulose ether for the request for controlled release. Viscosity of cellulose ether also affects the texture and resistance of gel. It is generally accepted that the dissolution of drugs from of tablets is slower for cellulosics with greater weight molecular. Normally, gel strength can be stabilized. at molecular weights greater than about 150,000. The weight molecular cellulose ether is preferably in the range of between 4,000-100,000. However, for drugs with a relatively low water solubility, can be used combinations of cellulose ethers including those with grades of lower viscosity. In the most preferred embodiment, the cellulose ether is HPMC, typically the polymer of choice for a speed control carrier in matrix systems existing hydrophilic substances for extended substance release active. Your popularity can be attributed to your safety, availability, general adaptability and its characteristics Physicochemical / mechanical. In addition, it is believed in the art that HPMC stimulates gel formation which is much stronger and more compact compared to other cellulosics. Mixtures can also be used. of HPMC with other cellulose ethers, for example in a proportion weighing 99: 1 to 1: 1. However, it is preferred that the HPMC be the cellulose ether predominant in the mixture. HPMC is a polymer of linear cellulose comprising anhydroglucose rings etherified, prepared by treating fibers cellulosic with caustic solution, which in turn is treated with chloromethane and propylene oxide. In the art, the HPMC is considered as an amphiphilic polymer, whose properties of solution are defined by the average number of methoxy substituents and hydroxypropyl per unit of glucose. In the field, DS are used and MS to express the average substituents of methoxyl e hydroxypropyl. DS is a measure of hydrophobic properties, while MS is a measure of the hydrophilicity of the polymer. In a principle the invention is not limited to a source of HPMC particular. A suitable HPMC candidate is characterized by a DS of approximately 0.1-0.5 and an MS of approximately 1.0-3.0, being characterized in this way by a predominantly hydrophilic nature. It is preferred that the total molar substitution is at least 1.0, preferably at minus 2.0, most preferably at least 2.5. So alternatively, in terms of weight percentages, it is preferred that the HPMC of the invention contains 15-35% by weight of methoxy groups and 2-15% by weight of units of hydroxypropyl. The HPMC can be used as a substituted cellulosic commercially available controlled release, for example as Dow Chemicals Metocel E, F or K. Good results are obtained by example for HPMC K 15 or HPMC-HM 15000 PA2208 as It is commercially available through Wolff Cellulosics, Germany).

Uncrosslinked carboxymethyl starch

The term "carboxymethyl starch" is considered as a synonym for the terms "starch ether" and "starch glycolate." Throughout the description and in the claims, together with their sodium counter-ion associated, it is conveniently abbreviated as SSG. SSG prepares typically from natural starch with monochloroacetate of sodium or monochloroacetic acid in alcohol under conditions alkaline Good examples of cross-linked SSGs are Primojel®, commercially available with DMV International (Veghel, Countries Low), and Explotab® (Mendel, Carmel, NY, USA / JRS Pharma, Germany). However, unlike the aforementioned SSGs in today's market, sodium carboxymethyl starch or glycolate of sodium starch used in the present invention is substantially uncrosslinked and has a degree of substitution (SSG-DS) preferably in the range of 0.1-0.5. In one embodiment the SSG-DS is preferably between 0.22 and 0.32, since that these values are in accordance with the Pharmacopoeia standards. In accompanying examples 4 and 5 (table 3 and 4) show that Primojel® and Explotab® are not suitable for this purpose. Do not However, it has been observed that the best results in terms of synergy have been obtained in cases where the SSG-DS is tall. Therefore, in a preferred embodiment the starch of the carboxymethyl has an SSG-DS of 0.28-0.4. In theory, the SSG-DS can be even higher, but difficulties arise in the process of preparation, where a high SSG-DS leads to a reactive mixture with a very somewhat viscosity degree so it is difficult to prepare at industrial levels. However, the expert in the matter you should be aware that this limitation can be overcome optimizing reaction techniques for example by changing the reaction temperature, or the ratio of ethanol / water and volume in the reaction mixture. Unlike cellulose ether applied in The present invention, the SSG is a charged polymer. In addition, the SSG It is completely hydrophilic by nature. However, since the SSG can be synthesized in a water-miscible organic solvent, such as ethanol, methanol and isopropanol, the surface of the SSG can contain some structural hydrophobic fractions, due to the three-dimensional folding of the molecules. Therefore, the interaction between cellulose ether and SSG cannot be limited to hydrogen bonding, but may also include interactions hydrophobic Especially when the dry ether mixture of Cellulose / SSG is exposed to an aqueous medium, hydrophobic interaction It can be dominant. The hydrophobic groups exposed in the surface in SSG can initially provide for the interaction of cellulose ether molecules with SSGs of nature more hydrophobic, while hydrophilic interactions can gradually become more dominant as the solution of cellulose ether and SSG. As a result, they can observe different dissolution rates for mixtures formed from different SSGs, in the most likely related way with its real production processes. However, the same synergistic trends reappear in all SSGs evaluated, all within the desired range of the invention. It has been observed that the best results are obtained when the synthesis implies a Ethanol / water mixture with a weight ratio between 4: 1 and 6: 1. As mentioned before, the SSG of the invention is substantially uncrosslinked. Unfortunately, in practice the Actual amount of cross-linking in the SSG is difficult to determine directly. Therefore, "substantially uncrosslinked" is understands by understanding SSG whose preparation route implies a small crosslinking or no crosslinking. However, it obtain optimal results with a small degree of crosslinking, in the context of the invention this is considered to be included in the term "substantially non-crosslinked". An excellent method of test to assess the suitability of an SSG in the context of the invention is to determine its sedimentation volume, which is clearly related to the dissolution rate of the substance active from the tablet. The accompanying examples serve as evidence of that. A substantially non-crosslinked SSG according to the present invention is characterized by a volume of sedimentation or high gel volume: the sedimentation volume increases with a decreasing degree of crosslinking. Yes 0.25 g of SSG dissolve or disperse in 100 ml of deionized water at 25 ° C, its sedimentation volume after 24 hours should be greater than 85 ml, preferably greater than 90 ml. By reference, an SSG completely uncrosslinked would show a settling volume maximum of 100 ml, while a highly crosslinked SSG, used from Conventional way as a disintegrant, it shows a volume of sedimentation of approximately 9-15 ml. Do not However, since cellulose ethers can interfere with the test results, the previous test only applies to "Pure" SSG, which means that the SSG is not contaminated by the presence of a cellulose ether material. This test is hereafter referred to as the "first volume test of sedimentation. "To determine the suitability of a starch of carboxymethyl in a mixture with a cellulose ether, such as HPMC, the first sedimentation volume test is extended by An additional stage of centrifugation: 0.25 g of the mixture are taken as sample and dissolve or disperse in 100 ml of water deionized After 24 hours of sedimentation at 25 ° C, the sample centrifuge at 6080 G at 25 ° C for 15 minutes. Stratum upper (not gelled) is decanted, the rest forms the volume of sedimentation or volume of the gel. A carboxymethyl starch substantially non-crosslinked in a mixture with an ether of the cellulose shows a sedimentation volume greater than 60 ml, preferably even more than 80 ml. Repeating the test above, with only a substantially non-carboxymethyl starch crosslinked shows a value of 100 ml. The examples show that a crosslinked carboxymethyl starch and thus inadequate would give a sedimentation volume of approximately 50 ml as much, in a carboxymethyl starch: ether ratio of 1: 1 cellulose. More carboxymethyl starch would reduce the volume sedimentation, while without carboxymethyl starch (only cellulose ether) would give a settling volume of zero. Though 100% HPMC (in the absence of SSG) would also involve a volume of 100 ml sedimentation according to the test conditions above, you can easily distinguish 100% pure HPMC from mixtures synergies of HPMC / SSG according to the invention, for example by performing a coloring method such as the Lugol test. The preparation SSG also involves a drying stage. However, drying It is considered to imply a kind of dehydration, which frequently causes the formation of a physical cross-linking. Chemical cross-linking between groups may also occur. hydroxyl and carboxyl in the SSG, especially at a low pH. For prevent the formation of uncontrolled crosslinking, you have to Be careful when controlling the drying stage. The expert in the matter you should know that the best drying method, which can be implementable in production, it can be determined experimentally.

The source of starch was not considered a factor limiter However, it is preferred to use a carboxymethyl starch of sodium prepared from potato starch, since it has proved in the past to be more effective in the disintegration of tablet than the SSG obtained from corn, waxy corn, wheat, tapioca rice or starch. Starch can also be pregelatinized, since the retention of its granular structure is not a requirement for use in excipient formulations according to some Monographs of Pharmacopoeia. The molecular weight of carboxymethylated starch is determined by its source, but it can be estimate between 100,000-50,000,000. Preferably the SSG is no longer crystalline, since its preparation involves the use of strong alkaline conditions, and its purification involves the addition of water and flash drying, which destroy the crystallinity of Starch grains greatly.

Synergistic mix

To reach the synergistic effect of excipient of the invention, cellulose ether and starch of carboxymethyl can be combined with the (s) active substance (s) in a release tablet slow or extended using tablet techniques known in the technique, such as direct compression, technologies dry and wet granulation, including, but not limited to, slow shear, fast shear and bed processes fluidized The release of the active substance is not influenced by the tablet production method used by the mixture of hydrophilic matrix of the invention; nor is it affected by the hydrophilic / hydrophobic nature of the active substance itself. He cellulose ether, preferably HPMC, and the SSG are present in the synergistic excipient in a weight ratio of between 9: 1 and 1: 3, preferably in the range of 7: 1 to 1: 2. They get better results for weight ratios less than 4: 1, in the way more preferably less than 3: 1, in particular less than 2: 1, in particular 1: 1 or less. It is preferred that the ether mixture of Cellulose and SSG are homogeneous, for example it is achieved by mixing. This allows complete interaction between the combined excipients a Once it comes into contact with water. The invention also relates to a slow or extended release tablet containing the proportions of excipients described above and one or more active nouns The tablet composition contains preferably the combination of excipients in an amount of a 10-60% by weight, more preferably of at least one 20% by weight, based on the total weight of the tablet. The composition in tablets preferably contain 30-50% in combination weight of excipient. It has been observed that a high percentage of the polymer mixture, especially in combination with a weight ratio of HPMC: SSG in the range of 2: 1-1: 2, it is preferable for a long profile of slow or extended release. Here you can see that the profile of drug release in a mixture of SSG / HPMC within the ranges mentioned is more sensitive to changes in the concentration of HPMC That for the HPMC only. However, it is recommended that the proportion actual to include in each individual formulation is determined experimentally.

The invention also relates to the use of the above-mentioned combination of cellulose ether, in particular of HPMC, and SSG in controlled release formulations. While the focus is on agent release Pharmaceuticals, both hydrophilic and hydrophobic, the combination of the invention can also be applied in controlled release of nutritious and nutraceutical ingredients.

With substantially non-crosslinked SSG, understand the SSG that provides a higher settling volume at 85 ml, preferably greater than 90 ml, in the first test of the previous sedimentation volume.

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Examples Example 1 Preparation of crosslinked and uncrosslinked SSG (a) Reaction conditions

120 grams of uncrosslinked native potato starch (Solani Amylum de Avebe, The Netherlands) or an equivalent amount of crosslinked potato starch, which was prepared according to the method provided in the literature [Yoneya et al ., "Influence of cross-linked potato starch treated with POCl_ {3} on GSC, rheological properties and granule size "; Carbohydrate Polymer 2003, 55: 447-457] were dispersed in 380 g of 90% ethanol, then 17.5 grams of demineralized water, 17.5 grams of SMCA (sodium monochloroacetate) and 7.5 were added with stirring g of sodium hydroxide granulate. The reaction mixture was heated at 70 ° C with stirring for 30 minutes. The reaction mixture was further stirred at 70 ° C for 6 hours. Subsequently, the reaction mixture was cooled to 50 ° C, and 47 grams of 3.3% HCl in 90% ethanol were slowly added to neutralize the remaining NaOH in the reaction mixture. The pH of the final product was controlled in the pH range of 5.5-7.0.

(b) Purification of SSGs

After filtration of the suspension neutralized using a Büchner funnel, the SSG cake obtained is dispersed in 380 grams of 90% ethanol, stirred at 45 ° C for 15 minutes and the suspension was filtered using a Büchner funnel. He Washing process and previous filtering was repeated. The product of final cake was dried using a fluidized bed dryer during 10 minutes at 60 ° C before use. The SSG prepared the way Above has a degree of substitution (DS) of approximately 0.2. Other SSGs with 0.3 and 0.4 were prepared under the same conditions simply varying the amount of SMCA and NaOH in proportion.

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Example 2 Relationship between DS and SSG dissolution level in the mixture of HPMC / SSG (a) Formulation of tablets containing a mixture of HPMC / SSG

To verify the DS effect of the SSGs (prepared as in Example 1) at the dissolution rate of the active substance, tablets containing HPMC / SSGs are they did using the following formulation, to form three sets of tablets with variations in the degree of substitution of sodium starch glycolate (DS = 0.2 / 0.3 / 0.4):

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20 of metoprolol tartrate (active substance) (Fagron, Germany);

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39% of lactose (DCL14 from DMV-Fonterra Excipients, Germany);

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20 of HPMC-W, that is hydroxypropyl methylcell (Walocel HM 15,000 PA 2208 from Wolff Cellulosics, Germany);

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20 of sodium starch glycolate substantially uncrosslinked with different degrees of substitution (DS = 0.2, 0.3 and 0.4) prepared according to Example 1;

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0.5% of colloidal silica (Degussa Aerosil 200); Y

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0.5% of magnesium stearate (BUFA, The Netherlands).

These components are dry mixed to give a homogeneous mixture. The quantities of the formulations are express in percentages by weight of the total mixture.

(b) Formulation of reference tablets

For reference, the previous formulation also it was prepared with the mentioned components and quantities of the same, except that the mixture of 20% HPMC-W and 20% of SSG was now replaced by 40% of Wolff HPMC-W (Walocel HM 15000 PA 2208 Cellulosics, Germany).

(c) Tablet preparations

The dried mixtures were compressed to produce 250 mg of tablets at a compression force of 10 kN using a Korsch EK0 eccentric press equipped with beveled drills flat and round with a diameter of 9 mm. The tablets are made individually weighing 250 mg of powder mixture before place the material in the wedge.

(d) Dissolution experiments

To determine the release profile of the tablets, dissolution tests were performed in 900 ml of deionized water using the USP 2 apparatus with stirring at 50 rpm. To track the metoprolol tartrate release profile, an ultraviolet spectrometry at a wavelength of 222 nm was used to analyze samples taken periodically from the solution medium. The drug release (dissolution) profile of the tablet containing metoprolol tartrate is given as a percentage of the content of the target drug released with the
weather.

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The average results of six tablets are shown in table 1, together with those obtained for 40% of SSG (SD 0.3; results taken from table 5). These data show that all SSG formulations of 20% HPMC / 20% different DS (0.2, 0.3 and 0.4) give an improved controlled release profile, compared to reference formulations with only 40% HPMC and 40% SSG. The tablets formulated by present invention show a drug release substantially slower or extended than the tablets of reference.

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TABLE 1 Dissolution of tablets with the weather

one

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Similar results were obtained for dissolution profile of theophylline, which has a pH dependent on water solubility, instead of the drug Metoprolol lipophilic tartrate used above.

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Example 3 Effect of the degree of cross-linking of SSG in the profile of drug release (a) Preparation of cross-linked SSGs with degree of different crosslinking

SSGs with a degree of crosslinking were prepared different according to the methods described in example 1. The degree of Crosslinking (XL,%) in the specific SSG was defined as follows way:

XL (%) = (CL / CL_ {max}) * 100%

Here, CL represents the amount of crosslinking agent used in the preparation of the corresponding SSG, while CL max = 0.3% (based on the amount by weight of starch) is the amount of crosslinker POCl 3 that it is generally used to prepare highly crosslinked SSG suitable as a disintegrant [see Yoneya et al ., "Influence of cross-linked potato starch treated with POCl_ {3} on GSC, rheological properties and granule size"; Carbohydrate Polymer 2003, 55: 447-457. Such disintegrating crosslinked SSG shows a settling volume of approximately 9-15 ml, as measured by the method described in example 4 (a). The variation may be due to the type of crosslinking agent, in this particular case POCl3.

(b) Formulation of tablets containing SSGs of different degrees of crosslinking

To investigate the effect of cross-linking the SSGs on the dissolution profile, tablets were made using the following formulation to form six sets of tablets with variation in the degree of cross-linking of sodium starch glycolate (XL = 0%, 4, 8%, 9.6%, 14.6%, 36.5% and 100%). Sodium starch glycolate with 100% -XL is an equivalent to that studied in the aforementioned publication of Yoneya et al .

Uniform dry mixes of:

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20 of metoprolol tartrate (Fagron, Germany);

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49% of lactose (DCL14 from DMV-Fonterra Excipients, Germany);

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15% of HPMC-W (Walocel HM 4,000 PA 2208 (Wolff Cellulosics (FROM)));

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15% of sodium starch glycolate substantially uncrosslinked with a degree of substitution of 0.3 prepared according to example 1;

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0.5% of colloidal silica (Aerosil 200 from Degussa, Germany); Y

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0.5% of magnesium stearate (BUFA, The Netherlands).

They were used as a reference ingredients and amounts thereof, replacing the mixture of 15% of HPMC and 15% of SSG by 30% of HPMC-W (Walocel HM 4,000 PA 2208).

(c) Preparation, dissolution and analysis

The preparation and analysis of the tablets were performed according to the procedure mentioned in examples 2c and 2d. The average dissolution results with six tablets Different formulations are shown in Table 2. Table 2 shows an excellent solution with the polymer blend combined obtained with substantially non-crosslinked SSGs. Increase grade of crosslinking decreases synergy to a point where the combination no longer improves dissolution.

TABLE 2 Dissolution of tablets with the weather

2

Example 4 SSG sedimentation, dissolution and crosslinking ratio alone (a) Determination of the sedimentation volume of SSG alone

The sedimentation volume of tablets that contains SSGs with different degrees of crosslinking was determined according to the following method: 0.25 g of each corresponding SSG is mixed in a 100 ml graduated tube with 100 mL of water deionized and measured after a 24-hour waiting period. He sedimentation volume corresponds to gel formation as is visible to the eye.

(b) Determination of t_ {50 \ text {%}}

t_ {50 \ text {%}} is defined as the point time in which 50% of the active substance has been released from tablet formulated with the corresponding SSG. Thus, t_ {50 \ text {%}} was interpolated from the data given in the example 3 (c). The sedimentation volume ratio of SSGs and t_ {50 \ text {%}} of the formulations containing the corresponding SSG is shown in table 3. Here, a volume of 100 ml sedimentation means that a separation of the unquantified phase (the SSG dissolves or disperses completely on the volume of the total continuous measurement (100 ml).

TABLE 3 Influence of cross-linking of SSGs in the sedimentation volume and t_ {50 \ text {%}}

3

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As shown in table 3, the volume of Crosslinked SSG sedimentation decreases with increasing degree of crosslinking. Slow or extended release performance increased dramatically when the SSG had XL = 14.6% or less and a sedimentation volume greater than 81 ml.

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Example 5 Sedimentation, dissolution and crosslinking ratio of SSG / HPMC

The sedimentation test of the example 4 (a), but now the sedimentation volume is determined for SSG having XL = 18.5%, SSG having XL = 12.9%, and SSG having XL = 0%, in the presence of different amounts of HPMC, including a reference without HPMC. By reference, the effects of SSG with XL = 100% without and in combination with HPMC also showed, using Primojel® and Explotab® commercially available as a source of SSG. To achieve this, the volume of sedimentation of powder mixtures containing SSGs and HPMC is determined according to the following method: 0.25 g of SSG and an amount HPMC variable was mixed in a 100 ml graduated tube with 100 mL of deionized water. After 24 hours the aqueous mixture is centrifuged at 6,000 rpm and at 6080 G at 25 ° C for 15 minutes. He upper stratum was decanted if visible. The volume of gel remaining in the centrifuge tube corresponded to the volume of sedimentation. To complete, table 4 also shows the sedimentation volume values recalculated if the weight of the total sample out of 0.25 g. These calculations were confirmed experimentally. The crosslinked values in table 4 are in relation to a value of 100% assigned to Explotab / Primojel highly crosslinked.

TABLE 4 Sedimentation volume in the presence or absence of HPMC

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Example 6 Effect of the SSG ratio: HPMC (a) Formulation with different proportions of SSG: HPMC varying from 3: 1 to 1: 3

Five tablet formulations were prepared as follows:

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20 of metoprolol tartrate (Fagron, Germany);

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39% of lactose (DCL 14 of DMV-Fonterra Excipients, Germany);

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0.5% of colloidal silica (Aerosil 200 from Degussa, Germany);

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0.5% magnesium stearate (BUFA, The Netherlands); Y

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40% of Total polymer, contained in different proportions:

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HPMC (Metolose 90H 4,000 2208 from ShinEtsu, Japan); Y

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SSG no crosslinked (DS = 0.3) prepared according to Example 1.

The proportions of HPMC and SSG studied were: 1: 0, 3: 1, 1: 1, 1: 3 and 0: 1.

(b) Dissolution test

Tablets of the formulations were prepared above and analyzed according to the procedure described in the examples 2 (c) and 2 (d). The average results of the dissolution of six tablets are shown in table 5.

The data shows that all excipients compounds containing 40% HPMC-SE / SSG in proportions varying from 3: 1 to 1: 3 showed release profiles of improved drugs, compared to SSG or HPMC alone.

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TABLE 5 Dissolution of tablets with the weather

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Example 7 Dissolution profile for different polymeric contents (a) Formulation of tablets containing a 30-40% polymeric excipient in the formulation

The following formulations of tablets:

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20 of metoprolol tartrate (Fagron, Germany);

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59-39% lactose (DCL14 from DMV-Fonterra Excipients, Germany);

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0.5% of colloidal silica (Aerosil 200 from Degussa, Germany);

-

0.5% magnesium stearate (BUFA, The Netherlands); Y

-

30-40% of polymer

-

HPMC (Metolose 90H 4,000 2208 from ShinEtsu, Japan); Y

-

SSG no crosslinked (DS = 0.3) prepared according to Example 1.

The HPMC: SSG weight ratio was 1: 1.

The results were compared with those for HPMC only (HPMC weight ratio: SSG = 1: 0).

(b) Preparation, dissolution and analysis

The tablets were prepared and analyzed according to the procedure described in examples 2 (c) and 2 (d). The average results of the dissolution of six tablets are shown in table 6. The combination in both cases shows (with 30% and 40% total polymeric mixture (HPMC: SSG = 1: 1) in the Enhanced drug release profile of the total formulation, compared to the one taken for the HPMC only in it Total percentage in the formulation.

TABLE 6 Dissolution of tablets with the weather

8

Example 8 Effect of HPMC with different viscosities (a) Formulation of tablets containing HPMCs with different viscosities

To show that the mix also shows the synergistic effect when using HPMC with a higher viscosity, it He used the following formulation:

-

20 of metoprolol tartrate (Fagron, Germany);

-

39% of lactose (DCL14 from DMV-Fonterra Excipients, Germany);

-

20 of HPMC-W, selected from:

-

Walocel HM 4,000 PA 2208;

-

Walocel HM 15,000 PA 2208 (both of Wolff Cellulosics, Germany);

-

20 of Uncrosslinked SSG (DS = 0.3) prepared according to Example 1;

-

0.5% of colloidal silica (Aerosil 200 from Degussa, Germany); Y

-

0.5% magnesium stearate (BUFA, The Netherlands)

These components were mixed to give a homogeneous mixture.

The same formulation was prepared as a reference, without SSG but with 40% HPMC.

(b) Preparation, dissolution and analysis

The tablets were prepared and analyzed according to the procedure described in examples 2 (c) and 2 (d). The average results of the dissolution of six tablets are shown in table 7.

TABLE 7 Dissolution of tablets with the weather

9

References cited in the description This list of references cited by the applicant has been collected exclusively for reader information. Do not It is part of the European patent document. It has been made with the greatest diligence; the EPO however does not assume any responsibility for possible errors or omissions Patent documents cited in the description

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EP 1382331 A [0002]

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WO 0200204 A [0002]

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WO 02070021 A [0002]

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US 6500459 B [0002]

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WO 2004066981 A [0002]

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WO 2004006904 A [0002]

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WO 9746592 A [0002]

Bibliography outside the patent cited in the description

Rahmouni et al . Charaterization of binary mixtures consisting of cross-linked high amylose starch and hydroxypropylmethyl cellulose used in the preparation of controlled release tablets. Pharm Dev. Technol. , 2003 , vol. 4, 335-348 [0002]

Yoneia et al . Influence of cross-linked potato starch treated with POCl_ {3} on GSC, rheological properties and granule size. Carbohydrate Polymer , 2003 , vol. 55, 447-457 [0010] [0019]

Claims (8)

1. Slow release excipient composition or extended containing a substantially carboxymethyl starch uncrosslinked and a nonionic hydrophilic cellulose ether. 2. Excipient composition according to claim 1, wherein 0.25 g of said formulation in 100 ml of deionized water after 24 hours at 25 ° C, if subjected to centrifugation at 6080 G at 25 ° C for 15 minutes, shows a sedimentation volume of more than 60 ml. 3. Excipient composition according to claim 1 or 2, wherein said cellulose ether is hydroxypropyl methylcellulose (HPMC). 4. Excipient composition according to any of the preceding claims, wherein said cellulose ether and carboxymethyl starch are present in a weight ratio between 9: 1 and 1: 3. 5. Excipient composition according to any of the preceding claims, wherein said starch of carboxymethyl has a degree of substitution in the range of 0.1-0.5. 6. Slow release tablet formulation or extended containing the excipient composition according to any of the preceding claims, further containing one or more active substances. 7. Tablet according to claim 6, wherein said carboxymethyl starch and cellulose ether are present together in an amount of 10% -60% by weight, based on total weight of the tablet 8. Use of the excipient composition according to any of claims 1-5 in a slow or extended release formulation.