KR20000069356A - Immediate Release Drug Delivery forms - Google Patents

Abstract

The present invention is directed to a drug delivery system having a property release property of an active agent useful in pharmaceutical dosage forms and processed by thermoforming techniques. Such delivery systems can be used as particles containing the active agent and the solubilizer contained in the dosage form.

Description

Rapid Release Drug Delivery Forms

Melt-blended formulations containing active agents and solubilizers are known in the art.

U.S. Patent No. 4,944,949 discloses a method for dissolving or melting together non-steroidal anti-inflammatory agents (NSAIDs) in a melt of nonionic surfactants such as poloxamers to form micelles (columns 5, 31). Row). : A micelle in which surfactant molecules are arranged in a spherical structure is aggregated with a hydrophilic region on the surface different from the hydrophobic region in the core. Herein, the ratio of the pharmaceutical surfactant is disclosed as 1: 5.7 to 1:50 in the twelfth column row 57.

U.S. Patent No. 5,281,420 discloses tebufellon as an anti-inflammatory agent in a solid dispersion containing 15 to 75% of tebufelone, 25 to 65% of poloxamer surfactant and other ingredients. Column 1, rows 35 to 51).

U. S. Patent No. 5,525, 355 relates to a laxative composition containing a poloxamer surfactant as a stool softener in a melt-blended state with a stimulant. The ratio of surfactant to stimulant is disclosed as 2: 1 to 20: 1 in line 22 of the second column. The composition is administered in a hard gelatin capsule.

EPO application 0 317 780, filed May 31, 1989, discloses rapid-release and sustained release formulations containing dihydropyridine calcium channel blockers, poloxamer surfactants and other components. The fast-release formulation contains hydroxypropylmethylcellulose to poloxamer / dihydropyridine complex derived from 0.15: 1 to 0.5: 1 water soluble cellulose (page 6, lines 48-49). The complex contains a drug: surfactant of 1: 1 to 1:10 (page 6, lines 25 to 27).

WO97 / 02017, published January 23, 1997, proposes an oral dosage form containing a solid dispersion containing the active ingredient in a poloxamer polymer prepared by dissolving or melt blending in a solvent. The ratio of active agent to poloxamer is from 0.1: 1.0 to 10.0: 1.0 (page 3, line 28).

U.S. Patent 4,727,709 discloses a liquid formulation containing a carrier system consisting of a hydrophilic component, a hydrophobic component and a solubilizing agent and an active agent. The hydrophilic component can be polyethylene glycol or polyoxyethylene / polyoxypropylene copolymer (see second column, lines 35-44).

U. S. Patent 5,456, 923 discloses a solid dispersion of a medicament present in a polymer made by extruding two materials and grinding the extrudate. This discloses polyethylene glycol or polyoxyethylene / polyoxypropylene copolymers using polymers as plasticizers (see third column, lines 33 to 34).

U.S. Patent 5,292,461 discloses pellets prepared by spraying an active agent with a humectant. Polyethylene glycols have been disclosed as lubricants (7th column, line 62) and as agents which affect the release of the active ingredient (8th column, lines 1 to 2). Polooxamers were mentioned as surfactants (7th column, line 65).

The present invention relates to a delivery system of an active agent having the property of rapidly releasing an active agent which is usually insoluble in water, a process for producing such a delivery system, and a product produced by the method. The method of the present invention for rapidly releasing an active agent from a pharmaceutical dosage form can be accomplished by thermoforming the active agent with a dissolving agent prior to preparing the dosage form.

The present invention consists of at least one active agent in the form of 50 to 80% by weight of insoluble solid particles in intimate contact with 20 to 50% by weight of a polymeric solubilizer, improved solubility, and a higher T _max of the drug. Provided are thermoforming drug delivery means useful for preparing a shortened form of a medicament.

As the solubilizer, a diblock copolymer containing polyoxyethylene and polyoxypropylene units is preferable, and Poloxamer 188 is more preferable.

As the active agent of the drug delivery system of the present invention, any one can be used as long as it can achieve the desired effect due to the improved release properties of the present invention and can be dissolved in the melt of the usual polymeric solubilizer. The agent is preferably selected from H ₂ -antagonists, non-anesthetic analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), anti-cholesterol agents, anti-allergic agents, migraine medications and combinations thereof, with ibuprofen being the most preferred active agent.

Rapid release formulations include formulations that reduce the T _max or the time it takes for the concentration of drug in plasma to peak depending on the drug or drug dosage administered. As used herein, “shortened T _max ” or “shorter T _max ” is a term that means enhanced absorption of the active agent at an initial time point when compared to the use of a conventional formulation for a medicament or a delivery carrier. It is assumed to be. The product according to the invention can release at least 80% active agent in about 5 minutes in a suitable pH environment.

The present invention may use any technique suitable for the preparation of the drug delivery material, including the liquid flash process and the extrusion process. A drug delivery material consists of a solid active agent in the form of being in homogeneous contact with the polymer solubilizer, embedded in or encapsulated or encapsulated in the polymer, or a combination of solubilizing or dissolving the active material. The material of the present invention can then be processed into particles, which can then be processed into conventional capsules, tablets or other dosage forms, all of which exhibit the rapid release properties of the active material. The formulations are typically for oral administration.

According to one aspect of the invention, there is provided a drug delivery product produced by thermally treating one or more active agents and one solubilizer to form a drug delivery means.

In the present application, thermoforming, thermoforming or thermoform processing, most active substances are not melted or mixed with the solvent, or are not dissolved in the solvent (melt blend), or It is to be understood that this refers to a process of exposing the active agent and the solvent to a sufficient amount of heat or other forms of energy such that the solvent does not form a single phase with the solvent when forming the liquid or liquid liquid phase. An important point of the thermoforming process is to control the tendency of the solubilizer and the active agent to combine during the heating process to form a single or dispersed phase. In thermoformed delivery systems, at least part of the dissolving agent must be encapsulated, encapsulated, or homogeneously mixed with the solid active agent particles. Formation of the mixed melt or solid solution of the active agent and the dissolving agent should be excluded or minimized as much as possible. This form is believed to inhibit the rapid release form of the present invention. Solid particles of the active material recrystallized from the mixed melt of the active agent and the solubilizer should also be minimized.

The liquiflash process is one of the thermoforming processes known in the art and is useful for use in the practice of the present invention. This requiflash process has been disclosed, for example, in U.S. Patent No. 5,683,720, filed November 4,1997. In addition to U.S. Patent Application Serial No. 08 / 874,215, filed June 13, 1997, U.S. Patents 5,445,769 and U.S. Patent 5,458,823 disclose some devices that can be used to prepare the thermoformed delivery formulations of the present invention by a liquiflash process. It is.

In addition to the liquiflash method, the extrusion method or other methods which do not mix-melt the dissolving or active agent to a significant extent may be used in the process of the present invention.

Compositions useful in the present invention consist of raw materials containing the following ingredients:

(a) 50 to 80% solid particles consisting of one or more active ingredients or agents; And

(b) 50-20% of the solubilizer.

Active ingredients useful in the present invention can be selected from a wide range of therapeutic agents and mixtures of these agents and pharmaceutically acceptable salts can also be used.

Active agents that can be relatively soluble in biological body fluids (eg, water) are examples of solid active agents that are particularly particularly enhanced in solubility and release properties by the delivery systems disclosed herein. Such agents include anesthetics, including nonsteroidal anti-inflammatory drugs (NSAIDs).

Useful NSAIDs include ibuprofen, diclofenac and their alkali metal salts; Phenopropene and metal salts thereof; Ketoprofen, naproxen and alkali metal salts thereof; And pyroxycam and salts thereof.

Combinations of various types of drugs in anesthetics as well as individual drug combinations may also be considered. In particular, non-anesthetic analgesics, and major intracellular activation of N-methyl-D-aspartate receptors such as morphinan, such as dextromethorphan or dextropan, or N-methyl-D-aspartate receptors. Combinations containing non-toxic substances, such as gangliosides, which block mechanisms, may be considered for use in the present invention.

The dissolving agent or dissolving agent used in the present invention may be a commercially available dissolving agent such as, for example, a generally solid diblock copolymer containing only polyoxyethylene units and polyoxypropylene units. Particularly useful are poloxamers containing polyoxyethylene and polyoxypropylene block units, particularly preferably containing 60 to 90%, preferably 70 to 80% polyoxyethylene units. Suitable polymers are those sold under the trade names "Lutrol", "Monolan" or "Pluronic" by BASF. Polooxamer 188 (Pluronic F68) is particularly effective. The diblock copolymer surfactants have an average molecular weight of about 7680 to 9510 [Handbook of Pharmaceutical Excipients (2nd Edition), 1994, pp 352-354]. Other useful "Pluronic" polymers are those represented by F87, F108, F127, and F237.

Another group of useful solubilizers are polyethylene glycol esters commercially available as "Gelucire" (Gattefosse), "Gelucire 50/13" is polyethylene glycol-32 glyceryl palmitostearate (HLB 13).

Solid particles produced from the delivery system of the present invention may be coated with one or more layers of pharmaceutical cortin material after formulation. However, no coating should be used that significantly alters the release form of the dosage form or particles, such as tablets. Useful coatings include decorative coatings, flavor coatings, coatings that degrade in the intestine, and coatings commonly used in the pharmaceutical art. Such a coating material will be present in an amount sufficient to function as a drug, i.e., a pharmaceutically suitable amount.

Suitable types and amounts of pharmaceutical excipients such as, for example, fillers, flavors, rheology modifiers, lubricants, diluents, etc., as illustrated in Table 1 below, may be combined with the particles of the delivery system prior to or during the preparation of the appropriate dosage form. . However, the excipients are not combined with the raw materials of the delivery system prior to the thermoforming process. The excipients or combinations thereof may be separately thermoformed, but they are not processed in the presence of active agent / solvent delivery system raw materials.

Solid diluents are typical excipients useful in formulating typical dosage forms and are generally extenders. These are typically present at weight concentrations on the order of 1/2 to 2/3 of the dosage system concentration.

Useful solid diluents are microcrystalline cellulose products with particle sizes of 20 to 200 μm, in particular Avicel PH101 (FMC) from Avicel.

Disintegrants may be used to aid in the release of the active agent from the formulation after taking the tablet. Useful disintegrants include croscarmellose sodium, polyvinylpolypyrrolidone (PVPP), and sodium glycol glycolate. Ac-Di-Sol, FMC's croscarmellose sodium product, is also very useful as Kollidon CL-M as micronized crospovidone, and mixtures may be used.

For example, one or more glidants such as sugar, talc, lactose, stearate and colloidal silica can be used, and Cab-o-sil M5, a colloidal silica from Cabot, is very useful.

Lubricants may also be used in the tablet compositions of the present invention, among which stearic acid, adipic acid, fatty acid esters, talc, magnesium stearate, inorganic oils and the like or mixtures thereof are preferable, in particular stearic acid manufactured by Sherex Chemical Co. The powder is very effective.

Other conventional pharmaceutical dosage forms of additives may also be used, for example, trace amounts of ingredients such as colorants, flavors, rheology modifiers, fragrances and stabilizers.

TABLE 1

Tablet ingredient list

Optionally, the delivery system particles of the present invention can be coated or encapsulated with a material that changes properties such as stability, taste, appearance, etc., but cannot change the property release properties of the present invention. Such coatings may contain one or more pharmaceutically acceptable polymers such as cellulose derivatives.

The thermoforming process and the liquiflash process in particular preferably comprise providing a component having a particle size of 2 to 500 μm, preferably about 5 μm (in the case of ibuprofen). A preliminary step to prepare the active material may require a shredding / crushing process. Next, the particles of the active substance and the solubilizer may be combined and used as raw materials in a suitable thermoforming apparatus, whereby the heat and centrifugal pressure conditions may be adjusted to cause morphological changes of the raw materials.

In the liquid liquiflash thermoforming apparatus, the solubility particles of the raw material may become "liquid form", losing their resistance to the flow of liquid. In this state, the material is physically converted by reduction from the original solid state to the "liquid" state and back to the solid state. During this process, the particles can also be operated by centrifugal or other shear forces, which forces are further applied to the "liquid form" conditions so that the solubilizer portion of the raw material can encapsulate the active agent in the form of at least some solid particles.

U.S. Patent Nos. 5,445,769 and 5,458,823, and U.S. Patent Application Nos. 08 / 330,412 and 08 / 874,215, describe in detail such liquid flash and flash flow processes.

Hereinafter, the present invention will be described in detail by way of examples.

Example 1 Ibuprofen Delivery System

3 kg of finely divided ibuprofen (IBP) and 2 kg of ground Poloxamer 188 were added to the Stephan mixer in (1) 1/2 of the dissolving agent; (2) all of the IBP; And (3) in the order of the remaining solubilizer. The ingredient materials were mixed for about 30 minutes. The mixtures were used as raw materials as follows:

Raw materials were placed in a 5-inch spinning head disclosed in U.S. Patent Application Serial No. 08 / 874,215, filed June 13,1997. The speed of the head was raised to 60 Hz while the elements to be heated were raised to the temperature obtained under liquid flash conditions (about 60 to 75 ° C.).

The rotating head pushed the material into its hole and allowed the product to free fall down a distance of 6-8 feet from the head portion. The products consisted of small spheres containing 60:40 IBP: solvent.

After solidifying completely, the No. 6 screen was used to crush the delivery system material.

Once crushed, the solid particles can be used in a delivery system, eg in a medicine bag or in powder form. Alternatively, the agent may be used in the form of a liquid, gel, tablet or capsule. Solid dosage forms are very effective. Optionally, the particles can be used to apply one or more coatings such as, for example, an aesthetic coating, a flavor coating, or a coating that can dissolve in the intestine prior to delivering the active agent into the body.

Example 2: Tests for Ibuprofen Dissolution

A. 40:60 IBP / Poloxamer

The same procedure as in Example 1 was carried out, except that particles containing 40% of IBP, which had not been previously micronized, and 60% of ground Poloxamer 188 were prepared. The spheres were subjected to a dissolution test using USP No. 2 method in phosphate buffer (30 ° C.) adjusted to pH 6.0.

The particles exhibited the following dissolution characteristics in a pH 6.0 medium:

B. 50:50 IBP / Poloxamer

The same procedure as in Example 1 was carried out, except that 50% of finely divided IBP particles and 50% of pulverized Poloxamer 188 were prepared.

Dissolution experiments were performed in pH 6.0 medium using the test method described in A above. The characteristics were as follows:

Example 3 Experiment on Ibuprofen Particles

In experiments on in vivo availability, the delivery system particles prepared according to Example 1 took longer to reach the highest plasma concentrations than when using commercially available IBP tablets (NUPRIN, Bristol-Myers Squibb Co.). (T _max ) is much shorter.

This experiment was designed to measure plasma IBP concentrations at various time points. The absorption rate of ibuprofen was shown to be enhanced at the initial time point, and the plasma concentrations over time in individual samples are shown below. T _max was determined from the concentration data, which was found to be 1.10 hours for the particles compared to 1.38 hours for commercial products.

One dose was administered to 10 healthy men and randomized during the course of practice. Plasma concentrations were measured prior to dosing, and plasma concentrations were measured at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 6, 8, 10 and 12 hours after administration.

In the following table, the rapid release delivery system is compared to NUPRIN tablets and the change in plasma concentrations in the subject over time at the initial time point is presented:

Example 6 Ibuprofen Tablets

Ibuprofen: Pluronic F-68 particles 60:40 formulation 58%; 35% of Avicel PH101; 3% croscarmellose sodium; 2% Cab-o-sil; And tablets containing 2% stearic acid were prepared. The components were combined in a V-blender and compressed and formulated on a Killian T200 rotary tablet compressor using an 8 × 16 mm caplet instrument.

Example 4: Ibuprofen Tablet Solubility Experiment

Solubility test was performed by USP No. 2 method (50 rpm) using phosphate buffer (900 mL, 37 ° C.) adjusted to pH 5.2 with 200 mg ibuprofen tablets containing 60:40 ibuprofen: release particles consisting of dissolving agent. . The solubility characteristics of the results were as follows.

For comparison, solubility tests were performed using 200 mg of ADVIL, available from Whitehall Labs (American Home Products).

Each tablet was found to contain the following: ibuprofen, acetylated monoglycerides, beeswax and / or carnauba wax, croscarmellose sodium, iron oxides, lecithin, methylparabens, microcrystalline cellulose, pharmaceutical glazes, povidone , Propylparaben, silicon dioxide, simethicone, sodium benzoate, sodium lauryl sulfate, sugars, stearic acid, sucrose, and titanium dioxide [Physician's Desk Reference for Non-prescription Drugs, 19th ed. (1998) p828].

Using the above conditions, ADVIL tablets were shown to have the following solubility characteristics:

It has been clearly seen that the delivery system material containing ibuprofen in the tablets of the present invention dissolves in properties compared to conventional formulations. 77% of the ibuprofen in the particles dissolved within 5 minutes, compared to 23% of ADVIL dissolved during the same time.

Example 6 Ibuprofen Delivery System

Undifferentiated Ibuprofen and Pluronic A 60:40 weight ratio mixture of F68 was extruded in MPV 2015, 15 mm double-blade co-rotating Baker Perkins extruder.

In the early stages of processing, Pluronic Only F68 surfactant was fed to the extruder. In all four temperature zones: barrel, die, and zones 2 and 3, the temperature was 73 ° C. Once a constant extrudate flow was achieved, a 60:40 mixture was fed into the extruder. At this point the temperature of the various zones was lowered to 55 ° C. While the extrusion process continues, at various time intervals from the beginning of the run, Teflon The extrudate sample was collected on a flat tray coated with a flask. During this time, the temperature was lowered from 55 ° C to 42 ° C.

The extrusion process was performed at an average speed of 31 rpm.

After completion of the above steps, the mixing was carried out in the same manner and the experiment was carried out using a product extruded at a higher temperature of 80 ° C. The process continued for about 15 minutes, during which three samples were collected.

Collected samples were ground in a Braun coffee grinder and passed through a 40 mesh sieve. Then, the sample passed through the sieve was subjected to solubility test by USP No. 2 method using phosphate buffer (37 ° C.) adjusted to pH 5.2. The solubility percentage of ibuprofen was measured for 5 minutes and the data of the results are summarized below:

While the present invention has been described based on specific embodiments, it will be readily apparent to those skilled in the art that various modifications may be made within the scope of the invention described in the spirit and claims of the invention.

The fast-release pharmaceutical formulations of the present invention are capable of achieving the desired efficacy by releasing the active agent in a faster time in a fast-acting drug, with significant improvements in speed compared to conventional formulations.

Claims (13)

A thermoformable drug delivery formulation useful for the manufacture of pharmaceutical formulations with improved solubility and shortened T _max , in the form of 50 to 80 percent by weight of insoluble solid particles in intimate contact with 20 to 50 percent by weight of a polymeric solubilizer. A thermoformable pharmaceutical delivery formulation consisting of at least one active agent and wherein said solid particulate active agent is soluble in a melt of polymeric solubilizer. 2. The thermoforming drug delivery formulation according to claim 1, wherein the solubilizer is a diblock copolymer containing polyoxyethylene and polyoxypropylene. The method of claim 2, wherein the one or more active agents are selected from H ₂ -antagonists, non-anesthetic analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), anti-cholesterol agents, anti-allergic agents, therapeutic agents for migraines, and combinations thereof. Thermoforming Drug Delivery Formulations. 4. The thermoforming drug delivery formulation according to claim 3, wherein said active agent is ibuprofen. 4. The thermoforming drug delivery formulation according to claim 3, wherein said active agent versus solubilizer is 40:60. 4. The thermoforming drug delivery formulation according to claim 3, wherein said active agent versus solubilizer is 50:50. 4. The thermoforming drug delivery formulation according to claim 3, wherein said active agent versus solubilizer is 60:40. A pharmaceutical formulation comprising a thermoforming pharmaceutical delivery formulation according to claim 1 and at least one pharmaceutically acceptable excipient. 9. The dosage form of claim 8, wherein the solubilizer is a diblock copolymer containing polyoxyethylene and polyoxypropylene. 10. The method of claim 9, wherein the at least one active agent is selected from H ₂ -antagonists, non-narcotic analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), anti-cholesterol agents, anti-allergic agents, therapeutic agents for migraines, and combinations thereof. Pharmaceutical formulations. 11. The dosage form of claim 10, wherein the active agent is ibuprofen. 12. The dosage form of claim 11, wherein the active agent has improved solubility and shortened T _max . The pharmaceutical dosage form according to claim 12, which is a tablet containing ibuprofen and a dissolving agent in a ratio of 60:40 to 80:20.