MXPA99003797A - Soluble form osmotic dose delivery system - Google Patents

Abstract

Disclosed is an osmotic pharmaceutical delivery system comprising (a) a semipermeable wall that maintains its integrity during pharmaceutical delivery and which has at least one passage therethrough;(b) a single, homogeneous composition within said wall, which composition consists essentially of (i) a pharmaceutically active agent;(ii) at least one non-swelling solubilizing agent which enhances the solubility of the pharmaceutically active agent;(iii) at least one non-swelling osmotic agent;and (iv) a non-swelling wicking agent dispersed throughout the composition which enhances the surface area contact of the pharmaceutical agent with the incoming aqueous fluid.

Description

OSMOTIC DOSE SUPPLY SYSTEM SOLUBLE The present invention relates to the field of osmotic systems for the delivery of pharmaceutical doses and preparations, in particular preparations that can be administered orally. Theeuwes et al., US Patent No. 3,916,899, discloses a preparation for the drug delivery that is said to release the pharmaceutical agent through openings in the wall of the tablet or capsules by the osmotic pressure difference established between concentration of the pharmaceutical agent inside the tablet or capsule and the external fluid medium of the patient when the medication is taken orally. See, also, Theeuewes et al., U.S. Patent No. 3,845,770 which discloses another preparation for delivery, by osmotic pressure difference, of a pharmaceutical agent. In this original type of proposal, the interior of the tablet had a hydrophobic core surrounded by a hydrophilic layer within the wall of the tablet. As such, the water entering the tablet remained in the hydrophilic layer and thus, very little medication was actually released. It has been believed that this proposal does not provide the pharmaceutical agent as completely or efficiently as previously thought. Therefore, a proposal was developed different to release the pharmaceutical agent. In this proposal the inside of the tablet or capsule is characterized by two layers, one containing the pharmaceutical agent (to be released again through holes in the wall of the tablet or capsule) and the other is a layer of material that is It swells when it comes into contact with water. These materials, which swell or expand to a state of equilibrium when exposed to water or other biological fluids, are known as "opium pyrolymers." This volume expansion is used to physically force the pharmaceutical agent out through the holes that have been placed. formed in the wall, layer or coating during processing.The pharmaceutical agent is mainly released as insoluble particles, which therefore have limited bio-availability.This has commonly been known as the proposed "" push / pull "". See, for example, U.S. Patent Nos. 5,422,123; 4,783,337; 4,765,989; 4,612,008; and 4,327,725. The patent literature taught that this proposal was necessary to provide adequate doses, at controlled rates and for long periods, of a wide variety of medications. Others ? osmotic delivery systems "have also been described, see, for example, U.S. Patent Nos. 4,609,374, 4,036,228, 4,992,278, 4,160,020, and 4,615,698, and the osmopolymers used in these types of systems. components whose functions are to swell when they interact with water and aqueous fluids. This swelling effect is defined in these patents as a property of absorbing fluid so much that they expand to a very high degree, usually having a volume increase of 2 to 50 times.

SUMMARY OF THE INVENTION Having arrived at the present invention it has been found that it is possible to efficiently deliver therapeutically effective doses, at controlled rates over extended times, of a wide variety of drugs without the need for swelling polymers to expand within the wall of the tablet, so as to physically force the medicament particles outwards as a means of use. The term "swelling" is also used herein, that is, the property that the present invention has been able to avoid, is used to have the same definition as in the patents described above, In addition, the invention makes it possible to supply agents that have limited aqueous solubility According to the preferred invention, an osmotic delivery system is provided, preferably in the form of a tablet, which distributes a therapeutic agent having limited solubility in water or physiological media without use of osmopolymers or swelling agents to deliver the therapeutic agents. Furthermore, according to the present invention, the therapeutic agent is incorporated into a composition that is capable of solubilizing the therapeutic agent, whereby the therapeutic agent is delivered in a predominantly solubilized form. In a preferred embodiment, the invention has appropriate solubilizing agents combined and, in the entire composition containing the pharmaceutical solubilizing agent (s), a "wick" agent that provides improved flow channels for the pharmaceutical agent that it has been predominantly made in its solubilized form by the solubilizing agent (s) while it is still inside the capsule tablet. In this way, the medicament is delivered to the outside through passages in the actual osmosis coating wall predominantly in its solubilized form, rather than by physical force in a particular form. Accordingly, in one aspect, the invention provides an osmosis system for pharmaceutical delivery comprising: (a) a semipermeable wall which maintains its integrity during the pharmaceutical delivery having at least one passage therethrough; (b) a single homogeneous composition within the wall, which composition contains: (i) a pharmaceutically active agent (ii) at least one non-swellable solubilizing agent which improves the solubility of the pharmaceutically active agent, (iii) at least one non-swellable osmotic agent, and (iv) a non-swellable wick agent dispersed throughout the composition, which improves the contact surface area of the pharmaceutical agent with the incoming aqueous fluid. The pharmaceutical agent is, in this way, released in a predominantly soluble form. Preferred non-swelling solubilizing agents include: (i) agents that inhibit the formation of crystals of the pharmaceutical agent or otherwise act in complexation with them; (ii) a micelle-forming surfactant with high HLB (hydrophilic-lipophilic balance), particularly non-ionic and / or anionic surfactants; (iii) citrate esters; and combinations thereof, particular combinations of complexing agent with anionic surfactants. Preferred inflatable osmosis agents include sugars with 10 or less rings, preferably 5 or fewer rings and more preferably rings. Examples include fructose, lactose, xylitol sorbitol. Preferred wicking agents include colloidal silicon dioxide d and can also function as wicking agent polyvinyl pyrrolidone and sodium lauryl sulfate.

BRIEF DESCRIPTION OF THE DRAWINGS The invention will also be described by reference to a brief description of each of the accompanying drawings. The brief description and the drawings are not a limitation of the invention. Figure 1A schematically illustrates the elemental osmotic system for dose delivery of the prior art. Figure IB schematically illustrates the osmotic dose delivery system of the prior art. Figure 2 schematically illustrates the osmotic dose delivery system of the present invention. Figure 3 shows, by means of the diagram, the percentage of release of nifedipine by means of dosage forms of the invention containing the formulations 1G (30 mg); 1C (30 mg); as shown in Table 1, and comparison with Procardia XL® (Pfizer, Inc., 30 mg). Figure 4 shows by means of a diagram the percentage of release of nifedipine by dosage forms of the invention containing the formulations 2B (47 mg); 2 (47 mg); and 2D (47 mg) as shown in Table 2, and comparison with Procardia XL® (Pfizer, Inc., 30 mg). Figure 5 shows by means of a diagram of percent release of nifedipine by the dosage forms of the invention containing the formulations 3C (30 mg); 3H (30 mg); as shown in Table 3 compared to Procardia XL® (Pfizer, Inc., 30 mg). Figure 6 shows by means of the diagram the percent of release of nifedipine by means of the forms of the invention containing the formulations 4H (30 mg); 4C (90 mg); as shown in Table 4 in comparison with Procardia XL® (Pfizer, Inc., 30 mg). Figure 7 shows, by means of the diagram, the percentage of release of nifedipine by means of forms of the invention containing the 5G formulations (60 mg); 5H (60 mg); as shown in Table 5 in comparison with Procardia XL® (Pfizer, Inc., 60 mg). Figure 8 schematically shows the percentage d release of nifedipine by means of the forms of the invention containing the formulations 6E (60 mg); 6F (6 mg); as shown in Table 6, compared to Procardia XL® (Pfizer, Inc., New York, 60 mg). Figure 9 shows the percent release of nifedipine by means of the forms of the invention which contain the 6F formulations (60 mg); with a sealed d coating of 1% ethylcellulose, as shown in the Table compared to Procardia XL® (Pfizer, Inc., New York, 6 mg).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The invention will be described in more detail with respect to numerous modalities and examples in support thereof. A semipermeable wall of the basic osmosis delivery system is composed of a polymeric material emptied or sprayed onto the tablet to give a layer weight of 2-15%. An example of a polymeric material includes, but is not limited to, cellulose acetate. The use of such a polymeric material requires plasticizer to increase flexibility, durability, and stability. In the case of cellulose acetate, examples of suitable plasticizers are triethyl citrate (TEC), propylene glycol (PG), a mixture of TEC and PG in ratios within the limits of 25 PEC plus 75% PG, up to 75% of TEC plus 25% of PG, Tween 80 other esters of polyoxyethylene sorbitan, triaceti dietilftalato, polyethylene glycol, mineral oil, tributi sebacate, and glycerol. The plasticizers are included as a suitable weight ratio of cellulose acetate to produce a semipermeable wall to achieve retention of the bioactive substance while allowing penetration of water up to the tablet nubbleo. The semipermeable wall of the tablet can contain at least one passage that communicates the contents of the core with the exterior of the device, supplying the beneficial medicament through the passages of the basic device for osmosis The size of a single passage can vary from 100 microns to 1000 microns, more preferred 300 to 900 microns, the most preferred 500 to 850 microns. Multiple passages may be present to communicate the contents with the outside of the tablet. A wicking agent is defined as any material that has the ability to attract water to the porous network of a supply device is included in the core of this type of tablet formulation. A wicking agent can do this with or without swelling, but those used in the present invention are non-swelling wicking agents. Some materiale can also attract water and swell, others can only function as wicking agents. These mech agents are characterized by having the ability to experience physical adsorption with water. Physical adsorption is defined as a form of adsorption in which the solvent molecules can freely adhere to the wicking agent surface by van der Waals interaction between the surface of the wicking agent and the absorbed molecule. In the case of a drug delivery device, the adsorbed molecule is mainly water or another biological fluid that is mainly composed of water. A wicking agent that attracts water, finally, will have a volume composed essentially of the volume of the wicking agent and the volume of water captured by it. A material that swells it will have a volume composed essentially of the volume of the wicking / swelling agent, the volume of the water trapped by it and an additional volume created by steric and molecular forces. The wick agent included in the formulations described in this invention creates channels or pores in the core of the tablet. This facilitates the channeling of water molecules through the core of the tablet by physical adsorption. The function of the wicking agent is to carry water to interior surfaces of the core or the tablet, by means of this, creating channels or an increased surface area network. For the purposes of this invention, the wicking agents do not swell to any appreciable degree. For bioactive agents with low water solubility, the mech agent assists in the delivery of the bioactive agent partially solubilized through the passage in the semi-permeable cover. Suitable materials to act as wicking agents include, but are not limited to, colloidal silicon dioxide, kaolin, titanium dioxide, silicon dioxide recovered from vapor condensation, alumina, niacinamide, sodium lauryl sulfate, low weight polyvinyl pyrrolidone. molecular, m-pyrol, bentonite, aluminum and magnesium silicate, polyester, polyethylene. Materials particularly suitable for the purpose of this invention include the non-swellable wicking agent, examples of which they are sodium lauryl sulfate, silicon dioxide and low molecular weight pyrrolidone. Preferred non-swelling solubilizing agents include (i) agents that inhibit the crystal formation of the pharmaceutical agent in other ways by complexation with it; (ii) with a micelle-forming surfactant of elevated HLB (hydrophilic-lipophilic balance), particularly anionic surfactants; (iii) citrate esters; combinations thereof, particularly combinations of the complexing agent with anionic surfactants. Examples of agents that inhibit crystal formation of the drugs, or otherwise act by complexation with this include polyvinylpyrrolidone, polyethylene glycol (particularly PEG 8000), α, β and β cyclodextrins and other modified cyclodextrins. Examples of high HLB d surfactants, micelle formers include n ionic and / or anionic surfactants, such as Tween 20, tween 60 or twee 80; polyoexilethylene or surfactants containing polyethylene, or other long chain anionic surfactants, particularly sodium lauryl sulfate. Examples of nitrate derivatives of esters which are preferred are alkyl esters, particularly triethyl citrates. The combinations of these types of non-swelling solubilizing agents are especially effective. Among such types d preferred combinations are agent combinations of complexation and anionic surfactants. Particularly preferred examples of such combinations are polyvinyl pyrrolidone with sodium lauryl sulfate and polyethylene glycol with sodium lauryl sulfate. Lubricants are also added to ensure proper tableting, and these include, but are not limited to: magnesium stearate, calcium stearate, stearic acid, polyethylene glycol, leucine, glyceryl behenate and hydrogenated vegetable oil. These lubricants must be present in quantities of 0.1-10% (w / w), with a preferred range of 0.3-3.0% (w / w). Preferred lubricants for tableting include but are not limited to: sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, stearic acid, glycerol behenate, sodium lauryl sulfate, polyethylene glycol, and hydrogenated vegetable oil. Particularly preferred lubricants are those which are soluble in water or gastric fluids or are easily emulsified. The combination of lubricants are especially effective. The lubricant combinations that are preferred are a small amount of hydrophobic lubricant with a large amount of an emulsifiable soluble lubricant. The concentration of use for lubricants extends from 0.25 to 10% with a preferred range of up to 4%.

The delivery system of the invention can be used to provide controlled release of a variety of therapeutically active agents. Examples include the following: cough inhibitors, such as dextromethorphan hydrobromide and codeine; antihistamines such as chlorpheniramine maleate, brompheniramine maleate, loratidine, astemizole, sodium diclofenac terfenadine; decongestants such as pseudoephedrine phenylephrine; antihypertensive agents such as nifedipine, verapamil, enalapril and salts thereof, metoprolol, metoprolol succinate, metoprolol fumarate, metoprolol tartrate; calcium channel blockers such as verapamil, diltiazam, nifedipine, nimodipine, felodipine, nicardipine, isradipine and amlodipine; antidiabetic agents such as glipizide and ibromectin; protone pump inhibitors such as or eprazol; H2 receptor antagonists with cimetidine, ranitidine, famotidine, nizatidine; carbamazepine, anti-Parkinson agents such as selegiline, carbidopa / levadopa, pergolide, bromocriptine, amantadine, trihexyphenidyl HCl; antiviral agents including herpes anti-virus agent such as acyclovir, famciclovir, fofscarnet, ganciclovir; anti retroviral agents such as didanosine, stavudine, zalcitabine, zidovudine, and another such as amantadine, interferon alfa, ribavirin, rimantadine; and other therapeutic agents such as cimetidine, propiomazine, phenytoin, tacrine, propiozam, proplazam. The system of the present invention is particularly applicable to therapeutic agents that are insoluble or poorly soluble in water or aqueous media at physiological p. In a preferred embodiment, the system of the present invention is used to dose nifedipine. In this preferred embodiment, the composition is free of agents which prevent the solubilization of nifedipine, such as the metals of group I and group II and salts thereof. Such compositions are the preferred osmotic agents or sugars.

Example 1 Granulation of nifedipine / tableting / coating A sufficient amount of water (TEC) or other suitable wetting agent is added to produce a good dispersion that atomizes and pumps well. Add 50 to 100% of PE 8000. Then, add 50 to 100% of the nifedipine to dispersion. Finally, add between 25 to 75% of Cab-o Sil® to the binder dispersion. Mix for ~ 2 minutes before atomizing. Also, other ingredients may be added to or removed from the dispersion as necessary. Also, a dispersion is not necessary, and the binder can be a PVP, PEG, sugar or other solution. binder. The solution can be aqueous or organic. In some cases, a hot melt granulation method may be preferred. In this case, the binder may be a molten wax, a mixture of waxes or other material. Load a fluidized bed bowl with osmagents (xylethol, sorbitol, lactose, fructose, inositol, etc.). Add 50 to 100% of the SLS, add the rest of PEG 8000"and add between 50-100% of the PVP K-25, add all or the remaining amount of nifedipine and other ingredients as required.Atmix the dispersion on the bed of powder with a spray rate of 20-50 g / min to produce granules of a suitable size for tabletting. (The rate of atomization will vary with the batch size.) The speed of the inflow of air and the temperature are adjusted to conserve the powder bed from over-granulation become excessively humid. (Usually, the range e 100-250 CMH and 40-60 ° C, depending on the size of the batch) Download the granulation and add the sodium lauryl sulfat remaining (SLS), polyvinyl pyrrolidone (PVP K-25), osmo agents, polyethylene glycol (PEG), nifedipine and Cab-o Sil® (colloidal silicon dioxide;; Cabot Corporation) mix in a V-mixer or appropriate mixer by 2-minutes or as necessary. r the proper lubricant, such as magnesium stearate (approximate 0. 5-1.5%) and mix 2-5 minutes or as necessary. Download the final mixer mix and tablet in a suitable tablet press. Cover the tablets with a fluidized bed coater or dryer with a spray rate of 30-100 g / min or greater (depending on the size of the batch). The coating solution is _. prepare by dissolving ~ 5% cellulose acetate, NF (National Formulary) in acetone or other suitable solvent, then add 25-45% plasticizers such as TEC or PG or mixtures thereof. The process can also be done by direct compression, highly shear granulation, hammered dry compression. In some cases, it may be desirable to modify the solubility characteristics of the osmagents, solubilizers, granulation or other ingredients to achieve a desired release profile. A method of modifying the release profile and using a hydrophobic coating method. Initially, all the ingredients can be granulated with 0-20% PV K25 or PEG 8000 or another aqueous binder or organic solution to ensure that the drug, sugars and solubilizer are evenly distributed in all the granules Following this procedure, a coating agent, ta as hydrogenated castor oil, vegetable oil hydrogenated, type I, ethyl cellulose, glyceryl monostearate, Gelucire® or near carnauba at 1-20% of the total weight of the formulation can be applied to 5-50% of the total granulation. The coating agent can be applied atomized by the top of a fluidized bed, wurtser column coating or rotor application; A container for coating and equipped with a sieve to cover granules can also be used. The hydrophobic agent can be applied in a molten state dissolved in a suitable solvent in which it will be atomized on the granules. Both parts of the granulation, of immediate and sustained release, can then be mixed perfectly using a V-mixer before tabletting. Altenertively, the method presented above can be applied to a component or combination of components of the formulation. One or more of the osmagents can be granulated alone or in combination with other osmagents, solubilizer or other core components. These granules can then be covered only or in combination with any other component of the core with the materials and methods described above. The coated granules can then be added to the remainder of the dry mix formulation, or can be actually granulated with the remainder of the formulation.

Alternatively, a hydrophobic granulation method can be used. In this method, wax and powder are mixed with the portion of the granulation to be covered (in the same percentage ranges already established). Non-powdered wax can be used to a fine particle size. Wax mixtures can be formed by melting the cer by adding the desired component, to allow the mixture to solidify and then sieve or grind the wax mixture to a fine particle size. The wax powder or wax mixture is then added to the fluidized bed with the portion d of the granulation to be covered. The materials are granulated increasing and controlling the inlet temperatures of the fluidized bed (inlet temperature ~ 60 80 ° C, outlet temperature ~ 40-60 ° C), to give rise to the steps of fusion / solidification involved in the process d granulation. In other cases, a chamfered device may be used to granulate. In this case, however, the temperature ranges would be applied to the substance used in the heating and cooling of the apparatus, such as steam, hot oil or water. For sustained-release agents that do not wax, the granulation processes can be carried out using standard granulation techniques, such as aqueous wet granulation or granulation with solvents (in the same range of percentages already established). The agent d Sustained release can be dissolved or suspended in the granulate fluid or it can be dispersed in the powders by being granulated. The granules are formed and dried and finally added to the rest of the formulation. Again, the above granulation techniques can be applied to a portion of the entire formulation or any component or mixture of components in the formulation. The sustained release granules can then be combined with the remainder of the formulation by the techniques previously described. Finally, a matrix technique can be used. This technique involves the addition of a wax powder to 5 30% of the total weight of the formulation, such as hydrogenated castor oil or glyceryl palmito stearate, glyceryl behenat, Gelucire®, PEG 8000 or any other matrix-forming agent, not inflatable, known by an expert in the art, to the formulation. The wax can be granulated with any component or combination of components of the formulation with 0-20% PVK K25 or PEG 8000 or other binder solution, or roller compaction or hammered method can be used in the formation of the granules. The granules are then added to the rest of the formulation using the methods established in principle. The modified release osmagents Solubilizers or granulation can then be tableted after the addition of a suitable lubricant. A single layer tablet will have all the components of the formulation mixed and compressed. One or more holes can be provided to give the proper release. One or more holes can be provided in the tablet. It can also be beneficial for a tablet to have a hole on both sides of the tablet, so that the optimal release rate is achieved. One or more holes can be provided to achieve the desired release characteristics. It is possible that any of the previously mentioned excipients in combination with the core of the tablet can lower the melting point. The temperatures at which the tablet should be exposed in a water-color coating process can be quite extreme (~ 60 ° C) to partially melt the core and change the physical-chemical behavior of the tablet in solution or stability. To avoid this change, Shire Laboratorie Inc was formulated a solvent-based color coating, consisting of a 1: 1 mixture of HPMC hydroxypropyl cellulose, and 1% of a colored aluminum lacquer dispersed in a 70:30 IPA solution. : Water. Because the color layer is solvent based, the temperature at which the tablets will be disposed in the coating process is significantly lower (~ 35-40 ° C). A delay of one or two hours before the start of the dissolution may be beneficial. To provide this time delay, a sealing cover may be added to the tablet. The sealing cover must provide a waterproof barrier for no more than two hours. Some polymers that can provide this type of cover include ethylcellulose, shellac, Eudragit RS. Other ingredients can be added to the polymers to modify the coating to achieve the desired delay time. U 1-10% weight gain should be applied to the tablets. The coating is applied as a solution or dispersion in aqueous or in organic solvent. The coating is usually applied in a coating container or fluidized lech equipped with a wurster column.

Example 2 Nifedipine Formulations The following are examples of formulations of the single, homogeneous composition within the tablet wall of the dosage form of the invention.

Table 1 * indicated in dispersion Table 2 scatter indicators Table 3 * indicated in dispersion ** Polyethylene glycol derived from castor oil (other suitable derivatives of castor oil or are described by the International Cosmetic Ingredient Dictionary (5th Ed.) Cosmetic Fragrance and Toiletry Association, Washington, DC (1993), for example on pages 479-481) Table 4 * indicated in dispersion Table 5 indicated in dispersion Table 6 Nifedipine Formulations Example 3 Comparative percentage of nifedipine release This example reports experiments comparing the percentages of nifedipine released by some of the above formulations in the dose delivery forms of the invention compared to Procardia XL® (Pfizer, Inc., 30 mg).

Materials and methods The dose delivery forms of the invention are placed in a Vankel dissolution apparatus containing simulated gastric fluid without enzymes and dissolved for 20 to 24 hours. Samples are taken from the dissolution medium periodically and analyzed by high performance liquid chromatography for the concentration of nifedipine. The calculated percent of release is plotted against time. The dosage forms of the invention and tablets of Procardia XL are tested in the same manner to produce effective comparisons.

Results Figure 3 schematically shows the release rate of nifedipine by the dosage forms of the invention containing the 1G formulations (30 mg); 1C (3 mg); as shown in Table 1, compared to Procardia XL® (Pfizer, Inc., 30 mg). Figure 4 shows schematically the percentage of release of nifedipine by the dosage forms of the invention containing the formulations 2B (47 mg); 2C (47 mg); and 2D (47 mg) as shown in Table 2 compared to Procardia XL® (Pfizer, Inc., 30 mg). Figure 5 schematically shows the release rate of nifedipine by the dosage forms of the invention containing the 3C formulations (30 mg); 3H (30 mg); as shown in Table 3 compared to Procardia XL® (Pfizer, Inc., 30 mg). Figure 6 schematically shows the percentage of release of nifedipine by means of the forms of the invention containing the formulations 4H (30 mg); 4C (90 mg); as shown in Table 4 in comparison with Procardia XL® (Pfizer, Inc., 30 mg). Figure 7 schematically shows the percentage d release of nifedipine by means of the forms of the invention containing the 5G formulations (60 mg); 5H (6 mg); as shown in Table 5 in comparison with Procardia XL® (Pfizer, Inc., 60 mg). Figure 8 schematically shows the percentage d release of nifedipine by means of the forms of the invention containing the formulations 6E (60 mg); 6F (6 mg); as shown in Table 6 in comparison with Procardia XL® (Pfizer, Inc., New York, 60 mg). Figure 9 shows the percent release of nifedipine by means of the forms of the invention containing the 6F formulations (60 mg); with a 1% ethylcellulose sealing cover as shown in Table 6 compared to Procardia XL® (Pfizer, Inc., New York, 60 mg).

Claims (13)

1. An osmotic pharmaceutical delivery system comprising (a) a semipermeable wall that maintains integrity during the pharmaceutical delivery and which has at least one passage therethrough; (b) a unique, homogeneous composition within said wall, which composition consists mainly of: (i) a pharmaceutical agent, (ii) at least one swellable solubilizing agent that improves the solubility of the pharmaceutical agent; (iii) at least one non-inflatable osmotic agent and (iv) or non-swellable wicking agent dispersed in the total composition.

2. The pharmaceutical delivery system of claim 1, wherein the pharmaceutical agent is released through at least one passage.

3. The pharmaceutical delivery system of claim 1, wherein the wall has a plurality of passages therethrough.

4. The pharmaceutical delivery system of claim 1, wherein the swelling solubilizing agent n is selected from the group consisting of: (i) agent that inhibit the formation of crystals of the pharmaceutical agent or, otherwise, act by complex ation with these; (ii) micelle-forming surfactant with high HLB (rocker hydrophilic lipophilic), particularly anionic surfactants; (iii) citrate esters; and combinations of the same.

5. The pharmaceutical delivery system of claim 4, comprising the combination of at least one complexing agent with at least one anionic surfactant.

6. The pharmaceutical delivery system of claim 5, wherein the combination is selected from the group consisting of: (i) a polyvinyl pyrrolidone and sodium lauryl sulfate and (ii) a non-swellable polyethylene glycol sodium lauryl sulfate.

7. The pharmaceutical delivery system of claim 1, wherein the at least one osmotic, non-inflatable agent is a sugar.

8. The pharmaceutical delivery system of claim 7, wherein the sugar has no more than 1 ring.

9. The pharmaceutical delivery system of claim 8, wherein the sugar has no more than rings.

10. The pharmaceutical delivery system of claim 9, wherein the sugar is selected from the group consisting of monosaccharides, disaccharides and trisaccharides.

11. The pharmaceutical supply system of l claim 9, wherein the sugar is selected from the group consisting of: fructose, lactose, xylitol, inositol and sorbitol.

12. The pharmaceutical delivery system of claim 11, wherein the sugar is covered with a hydrophobic material. The pharmaceutical delivery system of claim 1, wherein the non-swellable wicking agent is selected from the group consisting of colloidal silicon dioxide, polyvinylpyrrolidone and sodium lauryl sulfate.