MXPA99008044A - Sterol esters in solid dose forms as table - Google Patents

Abstract

The present invention relates to a stanol material in a form suitable for the manufacture of an oral dose, a method for producing the stanol material is also provided.

Description

STEROL ESTERS IN SOLID DOSE FORMS AS TABLETS FIELD OF THE INVENTION The present invention relates to esteral ester in the form of a tablet which is suitable for reducing cholesterol levels in a patient.

BACKGROUND OF THE INVENTION Several reports have described the use of plant sterols (ie, β-sitosterol) as dietary supplements for the reduction of serum cholesterol levels. It is generally accepted that the sitoesterol family of plant sterols reduces serum cholesterol by inhibiting the intestinal absorption of cholesterol. Recently, it has been shown that the saturated equivalent of β-sitosterol, β-sitostanol, is more effective in reducing the absorption of cholesterol in the intestine. In addition, the sitostanol itself is almost not absorbed, so it does not contribute at all to the concentration of serum cholesterol in vivo when consumed. These observations make β-sitostanol very likely used as an adjunct to reduce cholesterol levels in the serum. Typically, it has been necessary to incorporate the esteral ester into a suitable material such as margarine, in which the waxy nature of the sterol ester can be tolerated. There have been several reports in which it is described how the esterification of steels (tin) to a fatty acid or an edible oil produces a sterol (stanol) with improved solubility characteristics of micelles. For example, when the sitostanol is esterified to an edible oil such as rapeseed oil, a wax-like mixture of fatty acid esters with excellent lipid solubility is obtained. These sterol esters are conveniently incorporated into food products such as margarine. However, there is a continuing need for a tablet form of a sterol ester.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to a solid dose form consisting of: a support with a surface area range of about 100 to 350 m2 / g; an effective amount of stanol ester provided to reduce cholesterol; an effective amount of a surfactant system in the form of mixed micelles. The present invention also provides a method for producing a solid dosage form consisting of: providing the sterol ester in molten form; provide an effective amount of surfactant; provide a support with a surface area of about 100 to about 350 m2 / g; adding a sufficient amount of the support to the mixture of sterol ester and surfactant to form a flowable powder; and optionally, compressing the flowable powder to form a tablet. The above-described method uses the phase change from solid to liquid form under high temperature to charge the sterol ester on the support followed by a second phase change when the mixture is cooled to room temperature to help preserve the physical integrity of the product adsorbed.

DETAILED DESCRIPTION OF THE INVENTION Β-sitosterol is typically derived from wood or agricultural sources, such as soy-based mixtures. In addition to β-sitosterol, as used throughout this application, β-sitosterol also includes the β-sitosterol esters, as well as stanol and the sterol ester forms which are the oxidized form of the esterales. These derivatives are well known in the art and include patents of E.U.A. 5,244,887, E.U.A. 5,502,045 and E.U.A. 5,698,527. To be effective in reducing cholesterol in the bloodstream, it is necessary to consume less than about 1.5 grams, typically from about 0.25 to about 1.4 grams, preferably from about 0.5 to about 1.2 and most preferably from about 0.8 to approximately 1 gram of β-sitosterol per dose. The present invention is applicable to any of the following cholesterol reducing compounds in serum, including tinols, esterals, sterol esters, stanol esters, β-sitosterol, β-sitostanol and the like. Those skilled in the art will be able to carry out the present invention with any of those related materials. To be most effective when swallowed, the ß-sitosterol particle size should be in the range of 10 to 40 microns. Most preferably, the particle size should be from about 20 to about 35 microns. Any known grinding technique can be used to grind β-sitosterol. Suitable methods include pulverization, hammer milling, air mill molding and the like, of which milling with air mill is the most preferred.

Smaller particle sizes are preferred in which the resulting β-sitosterol product is more easily exposed to bile salts in the digestive tract. The handling properties of the product of smaller particle size are less desirable, resulting in a greater angle of rupture, greater angle of repose and degree of compression. The handling of the dispersible β-sitosterol product in water can be improved by increasing the particle size; however, it is believed that it is not good for the efficacy of β-sitosterol in reducing serum cholesterol.

Suitable surfactants are required to form the water-dispersible β-sitosterols. The present invention employs a double surfactant system. A surfactant in the system is monofunctional, while the second surfactant is polyfunctional. Monofunctional surfactants tend to be more hydrophobic, while polyfunctional surfactants tend to be hydrophobic. The two surfactant system employed in this invention creates a mixed micelle system that results in the water dispersible product. As used herein, monofunctional is defined as the ability of the surfactant to bind to β-sitosterol. The polyfunctional surfactant has the ability to bind to β-sitosterol as well as other surfactants. Surfactants useful in the practice of the present invention include polyglycerol esters, polysorbates, monoglycerides and diglycerides of fatty acids, propylene glycol esters, sucrose fatty acid esters and polyethylene derivatives of sorbitan fatty acid esters. These surfactants are well known in the art and are commercially available. Suitable polyglycerol esters include triglyceryl monostearate, hexaglyceryl distearate, hexaglyceryl monopalmitate, hexaglyceryl dipalmitate, decaglyceryl distearate, decaglyceryl monooleate, decaglyceryl dioleate, decaglycerol monopalmitate, decaglycerol dipalmitate, decaglyceryl monostearate, octaglycerol monooleate, octaglycerol monostearate and decaglycerol monocaprylate. Other useful surfactants include polysorbates made from the reaction product of monoglycerides or sorbitan esters with ethylene oxides. Examples of useful polysorbates include monoglycerides or diglycerides of saturated fatty acids, polyoxyethylene-4-sorbitan monostearate, polyoxyethylene-20-sorbitan tristearate, polyoxyethylene-20-sorbitan monooleate, polyoxyethylene-5-sorbitan monooleate, polyoxyethylene trioleate, 20-sorbitan, sorbitan monopalmitate, sorbitan monolaurate, propylene glycol monolaurate, glycerol monostearate, diglycerol monostearate, glycerol lactyl palmitate. Other suitable surfactants, with hydrophilic-lipophilic equilibrium values in brackets, [], include decaglycerol monolaurate [15.5]; decaglycerol distearate [10.5]; decaglycerol dioleate [10.5]; decaglycerol dipalmitate [11.0]; decaglycerol monostearate [13.0]; decaglycerol monooleate [13.5]; hexaglycerol monostearate [12.0]; hexaglycerol monooleate [10.5]; hexaglycerol mono-butter [12.0]; polyoxyethylene- (20) -sorbitan monolaurate [16.7]; polyoxyethylene- (4) -sorbitán monolaurate [13.3]; polyoxyethylene- (20) -sorbitan monopalmitate [15.6]; polyoxyethylene- (20) -sorbitan monostearate [14.9]; polyoxyethylene- (20) -sorbitan tristerate [10.5]; polyoxyethylene- (20) -sorbitan monooleate [15.0]; polyoxyethylene- (5) -sorbitán monooleate [10.0]; polyoxyethylene- (20) -sorbitán trioleate [11.0]. As will be appreciated by those skilled in the art, the hydrophilic-lipophilic equilibrium value for a surfactant is an expression of its hydrophilic-lipophilic equilibrium values, i.e. the balance of the size and concentration of the hydrophilic (polar) and lipophilic ( non-polar) of the surfactant. Lactic acid derivatives include sodium stearoyl lactylate and calcium stearoyl lactylate. The level of monofunctional surfactant is typically from about 1 to about 15 weight percent based on the final dry weight of the β-sitosterol product, preferably from about 2 to about 12, and most preferably from about 4 to about 10 weight percent. The level of polyfunctional surfactant is typically from about 0.5 to about 15 weight percent based on the final dry weight of the β-sitosterol product, preferably from about 2 to about 12, and most preferably from about 4.0 to about 0 percent by weight. The preferred monofunctional surfactant is TWEEN 80 and the preferred polyfunctional surfactant is SPAN 80. Suitable ratios of monofunctional / polyfunctional surfactants include from about 1: 6 to about 1.5: 1, preferably from about 1: 4 to about 1.3: 1, most preferably around 1: 1. The level of surfactant employed ranges from about 0.5 to about 8 weight percent of total surfactant system, preferably from 1 to about 6, most preferably from about 3 to about 4 weight percent.

It has long been known that increasing the concentration of surfactant in a co-crystallization of a drug poorly soluble in water leads to an increase in wettability. The present invention also employs a support surface with a high surface area. The support is a pharmaceutically acceptable material with the specified surface area. The support surface typically has a surface area of about 100 to about 450 square meters, preferably from around 200 to approximately 350 square meters per gram. The support can be an organic compound (containing carbon and hydrogen) such as xanthan gum, microcrystalline cellulose or an excipient used for the formation of tablets, preferably the support surface is an inorganic material (containing other compounds that are not carbon and hydrogen), most preferably selected from magnesium aluminosilicate, tricalcium phosphate, silicon dioxide and the like. The support is provided in an amount sufficient to form a flowable powder, which is typically provided in an amount ranging from about 5 to about 75 milligrams per tablet, preferably from about 50 to about 10 and most preferably from about 40 to 100. approximately 20 mg per tablet produced. The present invention also contemplates the inclusion of pharmaceutical ingredients including sweeteners, disintegrators, lubricants, fillers, binders and adhesives, excipients, colorants, preservatives and the like. The present invention employs a phase change of the sterol ester from solid to molten forms under elevated temperature to charge the sterol ester onto the solid support followed by a second phase change when the mixture is cooled to room temperature to help preserve the physical integrity of the tablet. Typically, the sterol ester is heated to a temperature of from about 100 to about 45 ° C, preferably from about 70 to about 50 and most preferably from about 62 to about 56 ° C. One technique for measuring the effectiveness of the sterol ester system is through the size of the resultant micelles formed when placed in water. The size of the micelles formed in the suspension can be measured using a turbimeter. The greater the turbidity, the greater the formation of micelles. It is expected that the highest turbidity, ie the largest micelles provide a more effective form of β-sitosterol to reduce cholesterol when consumed. The preferred turbidity levels are greater than about 1250, preferably greater than 2500 and most preferably greater than 3000 Netallic Turbidity Units (NTU). As used herein, turbidity is the same as defined herein.

United States Pharmacopeia (Pharmacopoeia of the United States), the effect of light scattering of suspended particles and turbidity as the measure of the decrease in incident beam intensity per unit length of a given suspension. The scale of turbidity values is from 0 to 20,000 NTU. As a reference point, the turbidity of the water is 0. The turbidity of the samples was measured at room temperature. After the sterol ester is mixed with the catalyst support, the mixture is allowed to cool to room temperature once more allowing the material to solidify. The solidified material is then mixed with suitable materials and is ready for tabletting. Tableting is accomplished by well-known techniques, including mucilage formation, chemisation, and rotating tablet compression. The 'tablets include gelatin-coated materials, caplets, capsules and the like. An advantage of this invention is that it offers an attractive tablet to the consumer, resistant to tampering, in which a minimum amount of excipients is needed. Another advantage of this invention is the potential 5 to increase the bioavailability of the sterol ester. Since the cholesterol lowering efficiency mechanism of the sterol ester is believed to involve incorporation into Gl micelles, any dosage form must provide a rapidly dispersible molecular state. This is ensured by supplying a solid solution of sterol esters and surfactants, which is a molecular dispersion. It has been shown that solid dispersions of drugs hardly soluble in water increase dissolution rates in vitro and bioavailability in vivo. Another advantage is the preparation in a container that is fast and economical.

The following examples are provided to illustrate the present invention. The present invention is not limited to the modalities presented below. Unless otherwise indicated, all units should be considered in percent by weight.

EXAMPLE 1 Preparation of solid supported sterol ester using a preferred surfactant mixture The stanol ester (Rasio) was melted in a beaker with warm water mantle. A liquid surfactant system in mixed micelles was added to the molten product and stirred until homogeneous. In this example, a mixture of Tween 80 / Span 80 (ICI Chemcals) was added in a ratio of 1: 1. Portions of magnesium aluminosilicate (Neusilin US2) or tricalcium phosphate were added with stirring and the resulting effect on the volumetric properties were monitored from the suspension, to pass through granulation to a free flowing dry powder (A) giving as a result an exemplary composition in final weight percent preferred as 52.9% stanol ester, 10.1% Tween 80, 10.6% Span 80 and 26.5% Neusilin US2. The mixture was removed from the beaker and allowed to cool. The mixture showed an excellent powder flow, it was wetted and spontaneously dispersed by adding it to running water at room temperature.

COMPARATIVE EXAMPLE Preparation of stanol ester supported on solid using a mixture of incorrect surfactant A mixture prepared in a method similar to Example 1 was made substituting Tween 80 for Tween 40 (both available from ICI Americas). The mixture showed excellent powder flow but was not wetted or dispersed upon addition of water at room temperature. This illustrates the importance of the mixed micelles surfactant system in this invention.

EXAMPLE 2 Prototype of ingestible, directly compressible stanol ester tablet A portion of the product of Example 1 was mixed in powder with % by weight of sodium starch glycolate. The new mixture was manually compressed at 908 kg force for approximately 30 seconds on a Carver hydraulic press using a round 1.75 cm flat face beveled edge tool. The test tablets contained 418 mg as free stanol. The compact tablets were ejected with a surprisingly low friction force. The tablets produced showed spontaneous surface wear and were approximately 10% dispersed after standing for one minute in unstirred deionized water at room temperature.

EXAMPLE 3 Prototype of chewable tablet directly compressible A portion of the material made in Example 1 was powder mixed with xylitol, aspertame and artificial watermelon and strawberry flavors. The mixture was compressed under identical conditions to the prototype ingestible tablets, as in Example 2. The tablets were again expelled without difficulty, in the absence of any additional lubrication. A solid dispersion (solid solution mixtures of active (s) with amphiphilic inert semi-solid excipient (s)) of Example 1 was carried out in a carrier (eg, polyethylene glycol, saturated polyglycolized glycerides, waxes, oils, microemulsions) which is soluble in water and solid / semi-solid at room temperature to a liquid at elevated temperature. The active ingredient first dissolves in a molten vehicle. With this molten material, then hard shell capsules or soft gels are filled in hot using existing technology. After filling, the mixture solidifies upon cooling, creating a solid or semi-solid filled capsule product.

EXAMPLE 4 An example of comparing the effects of the various adsorbate supports on the final tablet form was made using Neusilin (magnesium aluminum silicate), Tixosil (silicon dioxide) and Tri-Cal (tricalcium phosphate) to create adsorbate of Stanol ester (SEA). The stanol ester adsorbate preparation: an accurately weighed amount of the stanol ester (Rasio Sito-74) was placed in a beaker with hot water (hot water circulator) equilibrated at 57 ° C. The stanol ester was allowed to melt in the liquid phase.

When the stanol ester completely melted, small portions of a adsorbate stirred slowly in the liquid. The adsorbate material was added continuously until the stanol ester liquid was completely incorporated on the adsorbate. The resulting material formed a free-flowing powder or large granules. Grinding of stanol ester adsorbate granules: stanol ester adsorbate granules were dried in a hood during -30 minutes before grinding. After the granules were dried, liquid nitrogen was emptied into a micromolino (Scienceware). The granules were then placed in the mill and frozen with more liquid nitrogen.

Finally, the upper part of the mill was replaced and the granules were ground into a fine powder. Dry blending of the tablet formulations: the dry mixing of the active and the excipients in a swirl packaging bag prepared all the tablet formulations. The excipients in each formulation were accurately weighed on a scale, dry blended with a spatula in a pre-weighed dish and then transferred in a swirl package for continuous dry mixing. Tablet pressing: Dry mix formulations were poured into a 1.75 cm round die and pressed using a 1.75 cm round FFBE tool. The tablets were pressed manually for 3 seconds at 140.6 kg / cm2 with a Carver press. Disintegration tests (DT): the tablets were placed in a calibrated disintegration bath containing water at 37 ° C. The tablets were repeatedly immersed in a 900 ml water bath until completely disintegrated. This procedure was done visually and time was recorded with a stopwatch. Turbidity tests: after the tablets completely disintegrated in the previous disintegration tests, the water was placed in a small glass tube and homogenized. The tube was then placed in a 2100N Hatch turbidimeter and a reading was taken. The stanol ester adsorbates Neusilin and Tixosil formed a free-flowing powder, while the tri-Cal stanol ester adsorbate formed large granules. These large granules were then ground into a fine powder as described above. Five different formulations, which used the three above stanol ester adsorbates, were prepared and tabletted as described in the previous experiment. These formulations are shown in Tables 1-5 below.

TABLE 1 Chewable tablet formulation using Neusilin stanol ester adsorbate The formulation in Table 1 was prepared using Neusilin stanol ester adsorbate. As seen before, these tablets contain 500 mg of active stanol and have a large amount of sodium starch glycolate (25%). After pressing, the resulting tablets were slightly sticky on one side, but did not form a film or stick to the tool. The dissolution times were taken in four of the tablets, which completely disintegrated between 12 minutes 43 seconds and 13 minutes 47 seconds. The resulting solution gave a turbidity of 1253 NTU. The formulation of Table 2 was prepared using the stazol ester adsorbate of Tixosil. The resulting tablets contained 500 mg of active stanol and a large amount of sodium starch glycolate (25.7%). After pressing, the tablets were gently expelled and left no noticeable film. Disintegration times were taken for four of the tablets, which disintegrated completely between 3 minutes 54 seconds and 4 minutes 05 seconds. The turbidity of the solution was measured at 4398 NTU.

TABLE 2 Chewable tablet formulation using Tixosil stanol ester adsorbate TABLE 3 Chewable tablet formulation using tricalcium stanol phosphate ester adsorbate The formulation of Table 3 was prepared with the tricalcium phosphate stanol ester adsorbate. The tablets contained 400 milligrams of active stanol and a large amount of sodium starch glycoate. The tablets were not sticky nor did they leave film on the tool. The dissolution times were taken in the four tablets, which disintegrated completely in 2 minutes 08 seconds. The resulting turbidity was 3136 NTU. The formulation shown in Table 4 was prepared with the stanol ester adsorbate Neusilin. This formulation was made with a minor amount of sodium starch glycolate (8%), a greater amount of sugar excipient and pressed into a smaller tablet than the formulation in Table 1. A disintegration test was performed on one of these, tablets, which disintegrated completely in 27 minutes and 51 seconds.

TABLE 4 Chewable tablet formulation using Neusilin stanol ester adsorbate TABLE 5 Formulation of chewable tablet using tricalcium phosphate stanol ester adsorbate The formulation shown in Table 5 was prepared with the tricalcium stanol phosphate ester adsorbate. This formulation is different from that of Table 3 due to its lower amount of sodium starch glycolate (8%) and its tricalcium phosphate excipient. This formulation also differed in size (2.6 g) and amount of active stanol (500 mg). A disintegration test was performed on one of the tablets, which disintegrated in 4 minutes and 29 seconds. The resulting turbidity was 924 NTU.

The above formulations show that it is possible to make a chewable stanol ester tablet, which could be dispersed in an aqueous solution in 30 minutes. These formulations, when compared in terms of dispersion time, tackiness and limited use of expensive excipients, with the above formulations, are clearly the best. Of the five previous formulations, the one shown in Table 5 is the most feasible. Tricalcium phosphate is inexpensive, readily available and this formulation uses a relatively small amount of sodium starch glycolate. In addition, tablets made from this formulation were completely dispersed in water after 4.5 minutes. An improvement was carried out by combining the upper powder flow of Neusilin-based formulas and the faster disintegration times of the tricarcino-based formulations.

Claims (8)

NOVELTY OF THE INVENTION CLAIMS

1. - A solid oral dosage form consisting of: a support with a surface area range of about 100 to 350 m2 / g; an effective amount of stanol ester provided to reduce cholesterol; an effective amount of a surfactant system in the form of mixed micelles.

2. The oral dosage form according to claim 1, further characterized in that the support is an inorganic material.

3. The oral dosage form according to claim 2, further characterized in that the support is selected from the group consisting of magnesium-alumina silicate, silicon dioxide and tricalcium phosphate.

4. The oral dosage form according to claim 1, further characterized in that the stanol ester is provided in an amount of less than about 1.5 grams.

5. A method for producing a solid oral dosage form consisting of: providing the sterol ester in molten form; provide an effective amount of surfactant; provide a support with a surface area of about 100 to about 350 m2 / g; adding a sufficient amount of the support to the mixture of sterol ester and surfactant to form a flowable powder; and optionally, compressing the flowable powder to form a tablet.

6. - The method according to claim 5, further characterized in that the support is an inorganic material.

7. The oral dosage form according to claim 5, further characterized in that the support is selected from the group consisting of magnesium-alumina silicate, silicon dioxide and tricalcium phosphate.

8. The oral dosage form according to claim 5, further characterized in that the stanol ester is provided in an amount of less than about 1.5 grams.