KR100234446B1 - Sustained-release tablet containing hydroxypropyl methylcellulose, binder, hydrophobic elements, and water-soluble medicament - Google Patents

Abstract

Sustained or sustained release tablets are described. Tablets of the invention include water-soluble agents, sustained hydroxypropyl methyl cellulose, pharmaceutical binders, and hydrophobic components.

Description

Sustained-release tablets containing hydroxypropyl methylcellulose, binders, hydrophobic ingredients, and water-soluble agents

1 is a graph showing the average release profile of 750 mg of niacin tablets prepared according to the present invention.

2 is a graph comparing the average release profile of niacin (500 mg) tablets prepared according to the present invention and commercially available extended-release niacin (500 mg) capsules.

The present invention relates to a controlled release tablet containing hydroxypropyl methylcellulose, a binder, an internal hydrophobic component and a water soluble agent. This tablet may be formed by wet granulation techniques.

Sustained or sustained release products for oral administration are known and widely used. Hydroxypropyl methylcellulose is used in these products. In such tablets hydroxypropyl methylcellulose is believed to partially hydrate on the tablet surface to form a gel layer. The rate of hydration and gelation of the hydroxypropyl methylcellulose tablet spread affects drug release from the tablet and contributes greatly to the sustained release aspect of this product.

However, it has been difficult to formulate sustained release tablets of soluble agents and hydroxypropyl methylcellulose. The reason is, firstly, it was difficult to achieve the desired release profile or to control the release rate, which is a soluble to highly soluble drug. This is because the drug flows out of the tablet before hydration and gelation of hydroxypropyl methylcellulose occurs. Secondly, known tableting techniques, such as direct compression and wet granulation, may fail if a high proportion of soluble agent is required, regardless of the degree of solubility of the agent.

Bead coating technology may be used to form sustained release products. Such products typically include hard gelatin capsules containing the dispensed beads of the medicament. Soluble agents are available in these types of sustained release capsules. However, tablets have certain advantages over capsules, which are lost when using sustained release capsules of soluble therapeutic agents.

Tablets have several advantages over capsules. For some drugs, it is desirable for a patient to begin taking fewer doses and gradually increase the dose to the desired level over time. This can help to avoid undesirable side effects. Tablets may be preferred over capsules in that scored tablets can be easily broken to form small doses.

In addition, tableting methods, such as wet granulation, are generally simpler and less expensive than beads coating and capsule formation. In addition, tablets may be more stable for use because they are hardly tamperable.

Thus, in combination with the benefits of hydroxypropyl methylcellulose, the low ease and wetness of wet granulation, and the other benefits of tablet form for capsules in sustaining and controlling the release rate, the more sustained release product of a more soluble drug There was a demand for it.

The inventors of the present invention have an effective amount of sustained but negligible hydroxypropyl methylcellulose, a pharmaceutical binder that is sufficiently water soluble to allow wet over-degradation, an effective amount to effect wet granulation, to achieve the desired release rate. Sustained release tablets comprising an internal hydrophobic component and a water soluble agent have been invented.

Sustained release tablets include a medicament and a hydrophilic polymer matrix to achieve controlled, sustained or prolonged release of the medicament. Tablets may comprise a high proportion of water soluble agents and may be prepared by wet granulation standard techniques. Preferred release profiles can be achieved. The tablets may be lined to facilitate titration to the desired dose.

The medicament may be a suitable water soluble therapeutically active substance, usually administered orally. The most advantageous agents from the present invention by the present inventors are those that are highly soluble for immediate inclusion in effective sustained release tablets using hydroxypropyl methylcellulose. Solubility of the agent may range from about 0.1 to 30% (at 25 ° C.). This includes less soluble to highly soluble compounds according to the regulations provided by Remington Pharmaceutical Sciences.

The minimum amount of medicament or active drug in the tablets of the invention will typically be about 30% by weight and can range up to about 90% by weight based on the weight of the tablet. Within this range, generally less soluble agents can be incorporated in higher amounts.

Niacin with a water solubility of about 1.67 g / 100 ml (25 ° C.) is a drug within the scope of the present invention. Niacin is represented by the general formula C ₆ H ₅ NO ₂ and is also known as nicotinic acid. Niacin is commercially available from the supplier (Lonza and Ashland Chemical) as fine white crystals or white crystalline powder. Niacin will typically be present at a level of 50 intrinsic 85% by weight relative to the tablet. Other therapeutically active substances suitable for use in the present invention include morphine sulfate, chlorpheniramine hydrochloride, pseudoephedrine, codeine sulfate and diltiagen hydrochloride, aspirin, acetominophene and naproxen.

The most important mechanism by which drug release is controlled is through the use of hydroxypropyl methylcellulose. Hydroxypropyl methylcellulose present throughout the tablet is partially hydrated on the tablet surface to form a gel layer. The overall release rate and drug availability depend on the rate of diffusion of the soluble drug through the rate of wet gel and tablet corrosion. Hydroxypropyl methylcellulose having a substitution rate of methoxyl group of about 7-30% and a substitution rate of hydroxypropoxyl group of greater than 7% or about 7-20% is preferred for forming the gel layer. More preferably, the substitution rate of the methoxyl group is 19-30% and the substitution rate of the hydroxypropyl group is 7-12%.

Hydroxypropyl methylcelluloses vary in their viscosity, methoxyl content and hydroxypropoxyl content. Characteristics also vary. Some hydroxypropyl methylcelluloses are better sustained or have the ability to achieve controlled release of the drug. Other hydroxypropyl methylcelluloses have excellent binding properties but are almost unfavorable for sustained release. "Binding properties" means the ability to act as a binder to produce tablets by incorporating hydroxyl methylcellulose into an aqueous solution for wet granulation, for example, to spray onto anhydrous powder. Sustained hydroxypropyl methylcellulose is too viscous for use as a binder in wet granulation techniques.

Tablets of the present invention comprise about 5-30% by weight of hydroxypropyl methylcellulose having sustained release and negligible binding properties. Such hydroxypropyl methylcelluloses generally have a viscosity of at least about 1000 centipoise.

More typically, the viscosity will be at least about 4000 cps. For improved performance, the tablets will comprise about 5 to 20 weight percent, or more preferably 8 to 12 weight percent of sustained hydroxypropyl methylcellulose.

Preferred hydroxypropyl methylcelluloses having sustained release are hydroxypropyl methyl having substitution type 2208, nominal viscosity of about 100.000 cps (2% aqueous), methoxyl content of about 19 to 24%, and hydroxypropoxyl content of about 7 to 12%. Cellulose. Preference is given to “sustained” grades having a particle size of at least 90% through the # 100 USS mesh screen. Commercially available hydroxypropyl methylcellulose that meets the above requirements is Methocel K100MCR (commercially available from Dow Chemical Company).

The tablet also contains 2-15% by weight of a water soluble pharmaceutical binder. The binder or binder formulation acts as an adhesive to add strength to the tablet, thereby aiding in the manufacture of tablets by wet granulation.

Many suitable binders are known. These include polyvinyl pyrrolidone, starch, gelatin, sucrose, lactose, methylcellulose, hydroxypropyl methylcellulose and the like. In order to ensure good binding without the use of excess binders, we prefer to use about 2 to 8% by weight, more preferably about 2 to 5% by weight, particularly when preferred binding agents are used do.

Preferred water-soluble pharmaceutical binders for use in the present invention are hydroxypropyl methylcelluloses having binding properties. Such hydroxypropyl methylcelluloses typically have much lower viscosities than hydroxypropyl methylcelluloses having good sustainability. Generally, the viscosity of the 2% aqueous solution will be less than about 1000 cps, more typically less than 100 cps.

Preferred hydroxypropyl methylcelluloses for use as binders in the context of the present invention have a nominal viscosity of about 15 (2% aqueous), a methoxy content of about 28 to 30%, a hydroxypropyl content of about 7 to 12%, and 100% of the particles. Particle size through the USS 30 mesh screen and 99% of the particles have a particle size through the USS 40 mesh screen. Hydroxypropyl methylcellulose 2910, Methocel E15 from The Dow Chemical Company is a preferred binder because it meets the above criteria.

Other suitable binding hydroxypropyl methylcelluloses include metocell ESLVP, metocell E50LVP and metocell K3P. Methylcellulose metocell AISLVP can also be used.

Another binder we recommend is polyvinyl pyrrolidone, also known as polyvidone, povidone and PVP. Typical properties of commercial PVPs include densities of 1.17 to 1.18 g / ml and average molecular weights in the range of about 10, 000 to 360, 000. In general, higher molecular weight PVPs will be more suitable for use in the present invention. Suppliers include BASF Wyandotte and GAF.

An essential component of the invention is what we refer to as the hydrophobic component. The hydrophobic component allows wet granulation of the soluble agent with hydroxypropyl methylcellulose, if not readily achieved using standard wet granulation techniques. In the absence of such components, it has been found that the hydroxypropyl methylcellulose / pharmaceutical mixture is “doughy” such that particles or powders cannot be readily obtained.

Hydrophobic components include wax-like materials. Wax-like materials include generally insoluble solid materials having waxy hardness. This material must of course be digestible. Many such materials are known and known as waxes, for example beeswax, carnauba wax, candelilla wax, Japan wax, paraffin, hydrogenated castor oil, higher fatty acids (eg Palmitic acid, stearic acid and myristic acid), esters of the higher fatty acids (e.g. substituted mono-, di- and tri-glycerides), acetylated monoglycerides, glyceryl monostearate, glyceryl Tristearate, cetyl palmitate, glycol stearate, glyceryl tri-myristate, higher fatty alcohols such as cetyl alcohol, stearyl alcohol and myristyl alcohol, and mixtures thereof.

Two wax-like materials are preferred in the context of the present invention in terms of their immediate use in powdered form, at a reasonable price, ease of handling and their efficacy. These wax materials are hydrogenated vegetable oils and stearic acid. In general, hydrogenated vegetable oils consist mostly of triglycerides of stearic acid and palmitic acid and are commercially available. Preferred hydrogenated vegetable oils for use in the present invention are Lubritab Sold under the trade name from Edward Mendell, Co., Inc., New York. Lubritab The product has a volume density of 0.48 to 0.56 g per ml, a melting point of 61 to 66 ° C., a saponification value of 188 to 198, a maximum particle size distribution of up to 15% on a non-saponified material 0.8 and a 100 mesh USS screen, and 200 It has a typical particle size distribution of up to 35% on mesh USS screens. The advantage of this product is its availability in powder form. Similar hydrogenated vegetable oils are commercially available from Durkee under the Duratex trademark.

Typically stearic acid or octadecanoic acid can be prepared from fats and oils derived from edible sources, and commercially available stearic acid is typically stearic acid (C ₁₈ H ₃₆ O ₂ ) and palmitic acid (C ₁₆ H ₃₂ O ₂ ). Is a mixture of. Stearic acid is commercially available from many chemical suppliers, including vendors (Emery Industries and Mallinckrodt, Inc.).

Powdered stearic acid NF available from Mallinckrodt contains at least 40.0% C ₁₈ H ₃₆ O ₂ and at least 40.0% C ₁₆ H ₃₂ O ₂ , with the sum of these two components being at least 90.0%. Condensation temperature is 54 degreeC or more, and an iodine value is less than four.

The hydrophobic component should be present in an amount effective to allow wet granulation of the sustained release tablet. This amount is generally from 2 to 20% by weight of the tablet, depending on the solubility of the medicament. Higher concentrations will be required for more soluble agents. For good granulation results and sustained release, the hydrophobic component is preferably present at 5-15% or more preferably 6-12% by weight of the total tablet.

Other ingredients commonly used in tablet formulations such as external lubricants, dyes, fillers and extenders may also be used if desired. External lubricants or tableting aids include calcium stearate, stearic acid, hydrogenated vegetable oils, talc, corn starch, colloidal silicon dioxide, magnesium stearate and glyceryl behenate. We have found that the combination of glyceryl behenate, magnesium stearate and colloidal silicon dioxide is particularly effective as a tableting aid.

Typically, external lubricants applied to dry granules prior to tableting, if used, may be present in up to about 5% by weight of the total tablet. More preferably, the external lubricant will be present at 0.5-4% by weight or 1-3% by weight of the tablet to improve tableting.

Of course, dyes can be used for a more satisfactory tablet appearance. Many suitable dyes for purification are known and readily available.

Fillers or extenders can be used where necessary or desirable. When forming tablets containing a dose of niacin 250, 500 or 750 mg, fillers or extenders are not usually used because the medicament itself provides sufficient volume for the tablet. However, fillers or extenders may be preferred when the medicament is used in low doses. Many fillers or extenders, including calcium sulfate, dicalcium phosphate, tricalcium phosphate, lactose, sucrose, starch dextrose and microcrystalline cellulose, are known and readily available.

The process for forming the tablets of the present invention is a conventional wet granulation method which is a conventional or fluid bed. When these methods are used, a homogeneous mixture of hydrophobic components (flakes or powders) and dyes is formed. The binder is dissolved in water to form a binder solution. The hydrophobic component mixture, sustained release hydrocipropyl methylcellulose and the agent are granulated to a final moisture level of less than about 7%, preferably less than about 5%, using a binder solution. In a conventional manner, the granules are removed from the mixer and oven dried. The external lubricant is then mixed and tableted. As will be appreciated by those skilled in the art, the fluidized bed process does not require an oven drying step, instead the components are granulated and dried in one process.

Where niacin is a medicament, tablets containing doses of 250, 500 and 750 mg are useful. Higher doses, such as 750 mg, can cause side effects such as unpleasant scar and nausea if the treatment is not started at a lower dose. To administer tablets twice daily to titrate to standard 750 mg or less doses, lines may be drawn to facilitate breakdown into small doses. In particular, titrations with sustained-release tablets have been found to help prevent the side effects of niacin therapy.

Tablets made according to the present invention may have a desirable release profile that exhibits zero order absorption or constant release over time. Niacin tablets according to the present invention exhibit release characteristics of 10 to 35% within 2 hours, 40 to 70% within 8 hours and 90% within 24 hours after ingestion. Even more preferably, the profile of the niacin tablet releases 10-30% in 2 hours, 40-60% in 8 hours, and completely releases in 24 hours, and the tablet according to the invention exhibits this property.

The invention may be better understood by reference to the following examples which include preferred embodiments.

Example I

A 750 mg niacin tablet was prepared looking for the following ingredients:

Weight% mg / tablet

Niacin 73.07 750.0

Hydroxypropyl 2.50 25.7

Methylcellulose 2910

(Methocell E15LV.Dow)

Hydroxypropyl 9.74 100.0

Methylcellulose 2208

(Methocell K100MCR.Dow)

Hydrogenated Vegetable Oil 11.56 118.7

(Lubritab, Mendell)

Glyceryl Behenate 0.50 5.1

(Compritol 888)

Magnesium Stearate 1.50 15.4

(Mallinckrodt)

FD & C Red # 40 Lake Dye (40%) 0.13 1.3

(Colorcon)

Colloidal Silicon Dioxide 1.00 10.3

(Syloid 244)

To prepare tablets, 16 liters of water are heated to 95 ° C. in a stainless steel vessel. Methocel E15LV powder is added slowly while mixing until a uniform suspension is obtained. Adjust the impeller speed to prevent excess air from entering the solution through the vortex.

48 L of very cold water is slowly added and the mixture is sufficiently mixed until a clear solution is obtained and the temperature is below 20 ° C. Continue mixing for an additional 20 minutes.

Hydrogenated vegetable oils are sorted by size via USS No. 16 screens and added to the mixer. The dye is added to the mixer and mixed for about 5 minutes until the color distribution is uniform. The color mixture is then transferred to a ribbon blender. Niacin powder is added to the ribbon mixer and mixed for about 10 minutes. Methocel K100MCR is then added and mixed for an additional 10 minutes.

Methocel E15LV solution is sprayed and then mixed for 1 minute. The resulting wet granules are then sorted by size via USS No. 16 screen.

The sized wet granules are spread gently on the tray at about 2 kg per tray. The granules are dried in an oven at 230 ° F. with a moisture content of less than 5%. The oven dried granules were then transferred to USS No. Sort by size through 12 screens. After sorting by size, the granules are collected in a double poly-lined drum.

Three 200 kg batches each use 149.06 kg of niacin, 3.97 kg of metocell E15LV, 19.87 kg of metocell K100MCR, 24.84 kg of Lubritab hydrogenated vegetable oil, and 0.26 kg of FD & C Red Dye # 40 Lake 40% pure dye By the above method. These batch weights are weighed and compounded in a ribbon mixer. 3.0 kg of glyceryl behenate and 3.0 kg of magnesium stearate are then added to the ribbon mixer and the mixture is mixed for 5 minutes. The product obtained is compressed into 750 mg niacin tablets using a standard rotary press.

Example II

Make 750 mg of niacin economy as follows.

mg / kg used per tablet part

Niacin 750.00 312.500

Hydroxypropyl 24.00 10.000

Methylcellulose 2910

(Methocell E15LV, Dow)

Hydroxypropyl 94.10 39.200

Methylcellulose 2208

(Methocell K100MCR, Dow)

Hydrogenated Vegetable Oil 62.40 26.00

(Lubritab, Mendell)

FD & C Red # 40 Lake Dye (40%) 0.70 0.300

(Colorcon)

The niacin economy of Example II is formulated by fluid bed process. Half of this amount is used for the first granulation. In this granulation, 33.000 kg of deionized water is added to a stainless steel steam kettle and heated to 95 ° C. During mixing (avoid excess bubbles), Methocel E15LV and dye are added to water. 67.000 kg of cold deionized water is then added and mixing is continued for about 20 minutes. The mixture is cooled to 21 ° C.

Niacin, Methocel K100MCR and Lubritab hydrogenated vegetable oil are added to the fluidized bed vessel. These three components are granulated with Methocel E15LV solution. After the granulation solution is discarded, the material in the fluidized bed container is dried to less than 1% moisture.

The dried material is transferred to a transparent multi-line container. Using Sweco Sifter with 12 mesh screen, the granules are sized into clear multi-line drops.

Granules of the second batch are prepared in the same manner using half of the remaining ingredients. Two granules are then added to the ribbon mixer. These ingredients are mixed for 5 minutes. 6,000 kg magnesium stearate, 2,000 kg glyceryl behenate and 4,000 kg colloidal silicon dioxide are added to the ribbon mixer and mixed for 5 minutes. The material is transferred to a transparent multi-line drum and compressed into tablets containing 750.00 mg of niacin.

Two other formulations are shown below.

Example III

Chemical name mg / Tablet%

Niacin 750.0 78.125

Methocel E15LV 24.0 2.50

(Hydroxypropyl methylcellulose)

Methocel K100MCR 94.1 9.80

(Hydroxypropyl methylcellulose)

Lubritab 62.4 6.50

(Hydrogenated vegetable oil)

FD & C Red # 40 Dye 0.7 0.075

Magnesium Stearate 14.4 1.50

Compritol 4.8 0.50

(Glyceryl behenate)

Syloid 244 9.6 1.00

(Colloidal silicon dioxide)

Tablets having the composition of Example III are prepared using conventional and fluidized bed granulation techniques as preparation.

1 shows the average release pattern of six tablets having the general formula shown in Example III.

Purification of U.S.P. Dissolve at 37 ° C. in 900 ml of water at 100 rpm using a Hanson Dissolution Apparatus equipped with a rotating basket. Samples are taken from each dissolution vessel at 1, 2, 4, 8, 12 and 24 hours and the nicotinic acid content is analyzed by UV. The result shows a desirable release pattern.

Example IV

Chemical name mg / Tablet%

Niacin 750.0 76.220

Methocel E15LV 24.0 2.439

(Hydroxypropyl methylcellulose)

Methocel K100MCR 94.1 9.561

(Hydroxypropyl methylcellulose)

Lubritab 86.4 8.780

(Hydrogenated vegetable oil)

FD & C Red # 40 Dye 0.7 0.073

Magnesium Stearate 14.4 1.463

Compritol 4.8 0.488

(Glyceryl behenate)

Syloid 244 9.6 0.976

(Colloidal silicon dioxide)

Tablets having the composition of Example IV are prepared in the laboratory using conventional granulation techniques.

Example V

Chemical Name Weight% mg / Tablet

Niacin 73.07 500.00

Methocel E15LV 2.50 17.11

(Hydroxypropyl methylcellulose)

Methocel K100MCR 9.74 66.65

(Hydroxypropyl methylcellulose)

Lubritab 11.56 79.10

(Hydrogenated vegetable oil)

Compritol 888 0.50 3.42

(Glyceryl behenate)

Magnesium Stearate 1.50 10.26

FD & C Red # 40 Dye 0.13 .89

Syloid 244 1.00 6.84

(Colloidal silicon dioxide)

Tablets having the composition shown in Example V are prepared using conventional fluidized bed techniques. Tablets prepared according to the composition of Example V are compared to the release aspect of 500 mg of niacin, a conventional commercially available extended release capsule. Six samples of each product were subjected to U.S.P. at 100 rpm in 900 ml of 37 ° C. water. Dissolve using a Hanson dissolution apparatus equipped with a rotating basket. Samples are taken from each dissolution vessel over 24 hours. Nicotinic acid content is analyzed by UV. As shown in Figure 2, the tablets of the present invention follow a release profile similar to 500 mg of niacin, which is a commercially available extended release capsule.

Example VI

Chemical Name Total Weight% mg / Tablet

Niacin 73.07 250.00

Methocel E15LV 2.50 8.55

(Hydroxypropyl methylcellulose)

Methocel K100MCR 9.74 33.32

(Hydroxypropyl methylcellulose)

Lubritab 11.56 39.55

(Hydrogenated vegetable oil)

Compritol 888 0.50 1.71

(Glyceryl behenate)

Magnesium Stearate 1.50 5.13

FD & C Red # 40 Dye 0.13 .45

Syloid 244 1.00 3.42

(Colloidal silicon dioxide)

Tablets having the composition shown in Example VI were prepared using conventional fluidized bed techniques.

The above description and examples illustrate the invention. However, those skilled in the art can make various aspects without departing from the spirit and scope of the present invention, which is embodied in the appended claims.

Claims (11)

(a) about 5-30% by weight of hydroxypropyl methylcellulose having a viscosity of at least about 1000, a substitution rate of methoxyl group of about 7-30%, and a substitution rate of hydroxypropoxyl group of about 7-20%; (b) about 2 to 15 weight percent of a water soluble binder selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose or polyvinyl pyrrolidone having a viscosity of less than about 1000; (c) about 2-20% by weight of a hydrophobic component selected from hydrogenated vegetable oil or stearic acid and (d) a medicament having a solubility in water of about 0.1-30% by weight and having substantially zero absorption characteristics Sustained release non-coated tablets with a release profile of about 10-35% within 2 hours afterwards. The sustained release tablet of claim 1, wherein the water soluble agent comprises niacin and forms about 50 to 85% by weight of the tablet. The sustained release tablet of claim 1, further comprising up to about 5% by weight of an external lubricant. The sustained release tablet of claim 2, wherein the percentage of niacin released within 2 hours after ingesting the tablet is about 10-30% by weight. The sustained release tablet of claim 2, wherein the percentage of niacin released within 8 hours after ingesting the tablet is about 40-70% by weight. The sustained release tablet of claim 5, wherein at least 90% of the niacin is released within 24 hours after ingesting the tablet. The sustained release tablet of claim 2, wherein the sustained release tablet contains about 250 mg of niacin. The sustained release tablet of claim 2, wherein the sustained release tablet contains about 500 mg of niacin. The sustained release tablet of claim 2, containing about 750 mg of niacin. (a) about 5-20% by weight of hydroxypropyl methylcellulose having a viscosity of at least about 1000, a substitution rate of methoxyl group of about 7-30%, and a substitution rate of hydroxypropoxyl group of about 7-20%; (b) about 2 to 8 weight percent of hydroxypropyl methylcellulose, methylcellulose or polyvinyl pyrrolidone having a viscosity of less than about 1000; (c) about 5-15% by weight of hydrogenated vegetable oil or stearic acid and (d) a therapeutically active substance having a solubility in water of about 0.1-30% at room temperature, with substantially zero absorption characteristics Sustained release non-epilated tablets having a release profile of about 10-35% within 2 hours after ingestion. The sustained release tablet of claim 10, wherein the therapeutically active substance comprises niacin and forms about 50 to 85% by weight of the tablet.