Patent Application
20080075775
The present invention will be described in terms of a two-layer osmotic pump device, typically in the form of a tablet. The term “layer” is used for ease of description, but it is understood that a layer may be a compartment containing the described materials. One of the layers is the drug containing layer or drug layer containing the drug tamsulosin or a pharmaceutically acceptable salt thereof and a carrier as well as other ingredients as described herein. The other layer is the push layer which contains various kinds of osmopolymers, which are water-soluble hydrophilic polymers that, when dissolved, produce osmotic pressure in the drug layer. The push layer also contains water-insoluble volume-swellable polymers, which have high water absorption speed and high water absorption capacity so that they swell intensively when exposed to water. The swell of these water-insoluble polymers can have a mechanical push force on the drug release layer. Either or both of the drug layer and the push layer may contain an osmagent, also called an osmotic solute. Such agents are typically salts such as sodium chloride, potassium chloride, and the like or compounds such as mannitol, glucose, sucrose, or other inorganic salts, organic salts or carbohydrates.
The device will be surrounded by a wall comprising a semi-permeable material. This material is permeable to the passage of an exterior fluid present in the gastrointestinal tract such as aqueous fluids and other biological fluids, and substantially impermeable to the passage of tamsulosin or a pharmaceutically acceptable salt thereof. Such semi-permeable materials include, but are not limited to, acetate cellulose, ethyl cellulose, cellulose diacetate, cellulose triacetate, and the like.
There will be at least one passageway in the device, particularly in the form of a tablet, in the wall communicating with the layer containing the active ingredient and the exterior of the device in order to deliver the active ingredient from the device. Typically this is an orifice provided by drilling the tablet with a laser from the exterior to the first layer containing the active ingredient. The size of the orifice will in part determine the drug (active ingredient) release rate. The diameter of such an orifice in a typical device ranges from about 0.2 to 1.2 millimeters.
The present invention provides a two-layer or two-compartment osmotic pump device, preferably in the form of a tablet for delivering tamsulosin or a pharmaceutically acceptable salt thereof, preferably a hydrochloride, to the gastrointestinal tract for absorption into the body. In general, if tamsulosin hydrochloride is the active ingredient, the tablet will contain up to about 2 percent by weight of tamsulosin hydrochloride based on the total weight of the tablet. In the drug containing layer, the tablet will advantageously contain as a carrier for the tamsulosin one or more PVP polymers and/or PVP copolymers, which comprise from about 10 to 99 percent by weight of the drug containing layer. The exact ratio of PVP polymer and/or PVP copolymer used within the drug layer is ultimately dependent upon the constituent of the drug core and the desired drug release character. A useful PVP polymer is Povidone, a synthetic homopolymer of linear 1-vinyl-2-pyrrolidone groups with a molecular weight in the range of about 5,000 to 3,000,000, typically about 1,300,000. A useful PVP copolymer is Copovidone, a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in the mass proportion of 7:3, 3:2, 5:5 and 3:7, typically about 3:2. A typical molecular weight of Copovidone is about 50,000. Another useful PVP polymer is Crospovidone, a cross-linked 1-vinyl-2-pyrrolidone homopolymer.
The drug-containing layer also typically contains a glidant, such as silicon dioxide, a lubricant such as magnesium stearic acid and a colorant, such as an inorganic colorant to distinguish it from the push layer.
The drug-containing layer may also contain other ingredients such as hydrophilic sustained-release materials, dilutors, binders, and solvent. These additional sustained-release materials may be, for example, water-soluble osmopolymers such as acrylic acid polymers or copolymers, such as Carbomers, hydroxypropylmethyl cellulose (HPMC), and the like, or mixtures of two or more thereof. The drug-containing layer may also contain osmagents such as sodium chloride, lactose, mannitol, glucose, sucrose, fructose or mixtures of two or more thereof.
The second (push) layer of the device contains from about 10 to 80 percent by weight of the push layer of water-soluble osmopolymers, which can adjust the release ratio of the drug from the device, such as acrylic acid polymers or copolymers, such as Carbomers, hydroxypropylmethyl cellulose (HPMC), and/or PVP polymers and/or copolymers such as Povidone and Copovidone. The push layer also contains water-insoluble volume-swellable polymers, such as sodium starch glycolate, low-substituted hydroxypropyl cellulose, crosslinked carboxymethyl cellulose sodium, such as Croscarmellose sodium, and the like, or a mixture of two or more thereof. The push layer may also contain an osmagent such as sodium chloride, although the osmagent may also be contained in the drug-containing layer.
The push layer may also contain a glidant, such as silicon dioxide, a lubricant such as magnesium stearic acid and a colorant to distinguish it from the drug layer.
The colorants for the drug layer and push layer may be any one of several members of colorants, including inorganic oxides such as red ferric oxide, yellow ferric oxide, purple ferric oxide, black ferric oxide, or mixtures thereof.
Plasticizers may be typical plasticizers such as diethyl phthalate, ethyl phthalate, triethyl citrate, polyethylene glycol (PEG), or mixtures thereof.
Light blockers may be materials such as titanium dioxide, talc, silicon dioxide, or mixtures thereof.
Pore formers may be materials such as glycerin, propylene glycol, polyethylene glycol, water soluble inorganic salts, or mixtures thereof.
Solvents used in the manufacture of the drug layers may be materials such as acetone, water, ethanol, methylene dichloride, methanol, isopropanol, or mixtures thereof.
The membrane used to surround the device is a semipermeable composition such as cellulose acetate, cellulose diacetate, cellulose triacetate, or a cellulose alkanylate such as ethyl cellulose.
Methods of making osmotic pump devices are known in the art such as described by Santus et al., J of Controlled Release, 35, 1-21 (1995); and U.S. Pat. No. 4,765,989, the contents of which are incorporated by reference into the present specification.
A preferred method for making an osmotic pump device according to the invention is as follows. The drug layer is prepared by separately sieving a colorant, such as yellow ferric oxide, the PVP polymer and/or copolymer carrier, and other osmopolymer and/or osmagent to be used in the drug layer, through a 60-mesh sieve and homogeneously mixing the ingredients together with silicon dioxide which is used as a glidant. Then an alcohol water solution containing tamsulosin hydrochloride is sprayed into the dry mix, and the mixture powder is concomitantly granulated. Then magnesium stearate is added and mixed.
The push layer is formed by first homogenizing each ingredient by separately sieving through a 60-mesh sieve. Then the water-soluble osmopolymers, water-insoluble volume-swellable polymers, binders, osmagents and colorant are homogeneously mixed together with silicon dioxide as a glidant. An alcohol water solution is sprayed into the mixture to granulate it. Then magnesium stearate is added and mixed.
One layer is first compacted into the desired form and then the other layer is added and then the two layers are compacted together to form a two layer tablet. The semi-permeable membrane is coated on the outside of the tablet core and dried typically for about 24 hours at 45° C. A hole with the desired diameter, typically around 0.9 millimeters, is drilled into the wall adjacent to the drug layer by a machine or laser. The drilled tablet is coated with a moisture-proof film coat and dried again typically for about 12 hours at 45° C. This film coat can also improve the product appearance and offer color identification.
The controlled release tablet, according to the present invention typically maintains a relatively constant drug blood concentration for about 24 hours after administration. Advantageously, the release is not substantially affected by the environmental medium. That is, there is little individual variation in blood concentration due to variation in gastrointestinal peristalsis, pH, and food, with few side effects.
The daily dosage of tamsulosin or a pharmaceutically acceptable salt thereof may be determined on a case-by-case basis, but there is generally no particular limitation as long it is pharmaceutically effective for therapy or prevention of a particular disease or condition. For treatment of urinary dysfunction associated with BPH, typical daily dosages are in the range of about 0.1 mg 0.8 mg/day. Hence, tablets containing such amounts designed to deliver their payload of drug within 24 hours by sustained release would suffice.
The following examples are illustrative of the present invention, but they should not be considered as limiting the scope of the invention in any way.
Four kinds of dissolution medium simulating the gastrointestinal tract environment are designed to evaluate the effect of gastrointestinal peristalsis, pH and food on the drug releasing property.
Medium A represents standard condition of gastric fluid, Medium B represents the standard condition of intestinal fluid; Medium C represents the simulated condition of intestinal fluid (fasted condition); Medium D represents the simulated condition of intestinal fluid (fed condition). In use, administration under fasted conditions means administration without ingestion of food for at least 8 hours. Administration under fed conditions means that food is ingested within 30 minutes before or after administration.
The tablet releases drug slowly in the four selected media simulating the environment in vivo. The releasing properties are not affected by the media. This means that there is no statistically significant difference to restrict the clinical use. This provides a consistent and long-lasting curative effect with little individual variation and few side effects. Thus, the invention provides advantages of reduction of administration frequency, convenience for administration, little fluctuation of blood concentration, a long-lasting and steady curative effect, and few side effects.
These are several samples illustrating the invention.
Yellow ferric oxide, and Povidone (Plasdone K-90) and/or Copovidone (Plasdone S630) and/or sodium chloride are sieved through a sieve of 60 mesh and homogeneously mixed together with silicon dioxide. Then the solid mixture is added into a fluid bed granulator, and a pre-prepared alcohol solution containing tamsulosin hydrochloride is sprayed to affect granulation. Water residue percent, drug content percent, content uniformity and related compounds are determined. Then magnesium stearate is added and mixed. Granules of drug layer are formed.
First, all the ingredients are sieved through a sieve of 60 mesh separately, then Sodium CMS, HPMC, Carbomer, NaCl, Copovidone (Plasdone S630), red ferric oxide are mixed together with silicon dioxide. The mixture is added into a fluid-bed granulator, then 95% alcohol water solution is sprayed to make granulation. Water residue percent is determined. Then magnesium stearate is added and mixed. Granules of push layer is formed.
The two-layer tablet cores are compacted with the two types of granules. The diameter is 8 mm. Drug content percent and content uniformity of the two-layer tablets are determined.
The semi-permeable membrane is coated outside of the tablet core then dried at 45° C. for about 24 hours. The weight gain of tablet is controlled carefully during the coating process. The organic solvent residue amount is determined.
5. A pore with diameter of 0.9 mm is drilled in the wall adjacent to the drug-layer by machine or laser. The drug release profile is measured.
The tablet after drilling is coated by the moisture-proof film coat then dried at 45° C. for about 12 hours. Then quality analysis is conducted fully, including the drug content percent, drug content uniformity, drug release profiles, related compounds, residue amount of acetone, and others.
The drug release profile is measured in a type 2 dissolution apparatus (paddle) according to the China Pharmacopeia at 37° C. in 500 ml water at 50 rotations per minute. At 3, 5, 7, 12, and 16 hours, 10-ml are sampled respectively and the same volume of new dissolution media is immediately added. The samples are filtered with 0.45-μm micropore filter membrane as test solution. A portion of tamsulosin hydrochloride reference substance is dried at 105° C. for 2 hours, dissolved in water-acetonitrile solution (65:35) and diluted to obtain a solution having a known concentration of 0.5 mg per mL. A portion of this solution is diluted with water to obtain a solution having a known concentration of 0.4 μg/mL as reference solution. Then 80 μl of test and reference solutions are respectively injected into the chromatograph to determine the release of drug at the different times for each tablet. The detection chromatograph system is as follows: the column is ODS packed, the mobile phase is acetonitrile-perchloric acid solution (Dissolve 8.7 ml perchloric acid and 3 g NaOH into 1900 mL water, adjust it with NaOH solution to the value of pH equal to 2.0, then add water to the full scale of 2000 ml) (35:65, v/v). The flow rate is 1.0 ml/min. The wavelength of determination is 225 nm.
Using sample 1, the gastrointestinal tract environment in vivo is simulated with the four media above-mentioned and the effects of food, pH and gastrointestinal peristalsis on the drug release are evaluated. The results of release are shown in
Preparation of granules in the drug-layer: First, 0.6 g tamsulosin hydrochloride is dissolved in 500 mL 60% alcohol-water solution. Then yellow ferric oxide, Copovidone (Plasdone S630) and silicon dioxide are mixed homogeneously after being sieved through a sieve of 60 mesh. Then the solid mixture is added into the fluid bed granulator, and the pre-prepared 500 mL alcohol solution containing tamsulosin hydrochloride is sprayed to affect granulation. The bed temperature is raised gradually to dry the granulation. Then the drug content percent, drug content uniformity and the residue water percent are measured. Then, magnesium stearic acid is added, and mixed. Granules of the drug-layer are formed.
Preparation of granules in the push-layer: First, all the ingredients are sieved through a sieve of 60 mesh separately, then Sodium CMS, HPMC, Carbomer (Carbopol 971PNF), NaCl, Copovidone (Plasdone S630), red ferric oxide and silicon dioxide are mixed homogeneously. The mixture is added to the fluid-bed granulator, and 95% alcohol water solution is sprayed to make granules. The bed temperature is raised gradually to dry the granules. The residue water percent is determined, and then magnesium stearic acid is added, and mixed. Granules of the push-layer are formed.
Tablet pressing: The two-layer tablet cores are compacted with the two types of granules. The diameter is 8 mm. The hardness should be above 8 kilograms. Drug content percent and content uniformity of the two-layer tablets are determined. The weight range of the drug layer is 127-135 mg, and the whole tablet core weight range is 222-230 mg.
Tablet coating: The semi-permeable membrane is coated on the outside of the tablet core. The weight of the semi-permeable membrane is 33.2 mg per tablet. Then it is dried at 45° C. for about 24 h. The acetone residue amount is determined.
A pore with diameter of 0.9 mm is drilled in the wall adjacent to the drug-layer. The drug release profile is detected, and then it is coated with the aqueous-based film coating solution and dried at 45° C. for more than 3 hours. Then quality analysis is performed, including the drug content percent, drug content uniformity, drug release profiles, related compounds, residue amount of acetone, and others. Then it is packed to form the final product.
Six male beagle dogs, randomized to 3 groups, according to a Latin Square Design, 2 dogs per group, participated in a single-dose, 3-period, 3-crossover study.
In first period, the 2 beagles of group A took the reference drug (0.4 mg/2 capsules per dog) orally under fasting condition; the 2 beagles of group B took the test drug (0.4 mg/2 tablets per dog) orally under fasting condition; the 2 beagles of group C took the test drug (0.4 mg/2 tablets per dog) orally under fed condition.
After a 1-week washout period, the second cycle began. In second period, the 2 beagles of group A took the test drug orally under fasting condition; the 2 beagles of group B took the test drug orally under fed condition; the 2 beagles of group C took the reference drug orally under fasting condition. Then, there was a 1-week washout period.
In third period, the 2 beagles of group A took the test drug orally under fed condition; the 2 beagles of group B took the reference drug orally under fasting condition; the 2 beagles of group C took the test drug orally under fasting condition.
Four hours later after administration, the dogs were allowed to take food or water freely. 5 mL of blood sampling for each dog was done pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, and 48 hours after dosing of each period. The samples were centrifuged for 10 minutes at rate of 2500 rotations per minute to separate the plasma. And the plasma was preserved under frozen condition of −20° C. for determination. The adverse reactions of each dog were observed and recorded.
The order of administration was as followed:
The results show that the mean blood concentration of reference drug reaches peak point at about 1 hour after administration. And the mean blood concentrations of test drug under fasting and fed conditions maintain a higher level from 4-8 hours after administration and lower down to base level at 24 hours after administration.
The relative bioavailabilities of test drugs under fasting and fed conditions compared to reference drug are 88.02% and 92.42% respectively. Bioavailability means the amount and rate of unchanged active drug coming into systemic circulation.
According to the results of ANOVA, the Tmax of T is remarkably longer than that of R while the Cmax of T is remarkably lower than that of R. The results show that the test drug has the feature of controlled release. There is no remarkable difference of bioavailability between fasting and fed conditions for the test drug (P>0.05), indicating that the food effect does not affect the bioavailability of tamsulosin hydrochloride controlled-release tablets.
| Number | Date | Country | Kind |
|---|---|---|---|
| 200610153091.8 | Sep 2006 | CN | national |
