Liquisolid Compact Technique: A Novel Approach to Solubility Enhancement
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The present invention relates to powdered forms of liquid medications formulated to have both acceptable flow and acceptable compression characteristics, and methods of producing them. It is well established that the active ingredient in a solid dosage form must undergo dissolution before it is available for absorption from the gastrointestinal tract.
The rate of absorption liquisolid compacts patents and trademarks a sparingly water-soluble drug, formulated as an orally administered solid dosage form, is controlled by liquisolid compacts patents and trademarks dissolution rate in the fluid present at the absorption site, i. Since they exhibit poor and erratic dissolution profiles, most water-insoluble drugs are included by the FDA in the list of drugs having a high liquisolid compacts patents and trademarks for therapeutic inequivalence due to differences and inconsistencies in bioavailability.
Drug micronization, solid liquisolid compacts patents and trademarks, coprecipitation, lyophilization, microencapsulation and inclusion of drug solutions or liquid drugs into soft gelatin capsules or specially sealed hard shell capsules are some of the major formulation tools which have been shown to enhance the dissolution characteristics of water-insoluble drugs. Comparing various digoxin oral solid dosage forms, Ebert 1 has reported that soft gelatin capsule products demonstrated the highest and most consistent bioavailability, mainly due to the fact that the drug is already in solution.
Nelson, in his review 2points out that the availability of drug for absorption liquisolid compacts patents and trademarks various types of oral formulations, usually decreases in the following order: A more recent technique, entitled "powdered solution technology", has been applied to prepare water-insoluble drugs into rapid release solid dosage forms.
Powdered solutions are designed to contain liquid medications in powdered form, thereby possessing mechanisms of drug delivery similar to those of soft gelatin capsule preparations containing liquids. The concept of powdered liquisolid compacts patents and trademarks enables one to convert drug solutions or liquid drugs into liquisolid compacts patents and trademarks flowing powders by a simple admixture with selected powder excipients e. Several investigators have used a similar approach to improve the release profiles of several water-insoluble drugs.
Flow problems of such systems were addressed by the introduction of a new theoretical model for the principles underlying the formation of powdered solutions 3, 4.
Criticism of that work was based on the facts that the "angle of slide" test does not necessarily represent a realistic evaluation of flow characteristics and that liquisolid compacts patents and trademarks other than light mineral oil should have been also used to test the powders.
In subsequent projects 5acceptably flowing tablet formulations of clofibrate liquid drug and prednisolone dissolved in a non-volatile solvent systemmade according to the new mathematical flowability model, displayed consistently good flow properties and significantly higher dissolution profiles than those of commercial products, including soft gelatin capsule preparations. However, while evaluating the dissolution profiles of liquisolid tablets of clofibrate, compressibility problems were revealed.
Specifically, such liquisolid formulations of clofibrate could not be compressed into tablets of satisfactory hardness. It has been concluded that this phenomenon occurred due to respective amounts of liquid drug being squeezed out of the liquisolid tablet during compression. The present invention is thus directed to a method of converting a liquid medication into a liquisolid system, wherein the liquid medication is incorporated into a specific amount of carrier material, and the resulting wet mixture is blended with a calculated amount of coating material to produce a "dry" i.
Finally, various representative immediate and sustained release liquisolid tablet formulations and their flowability liquisolid compacts patents and trademarks compressibility evaluations and in-vitro and in-vivo release profiles compared to commercial products are included. The term "liquid medication" includes liquid lipophilic drugs and drug suspensions or solutions of solid water-insoluble drugs in suitable non-volatile solvent systems.
The term "water-insoluble drugs" includes those drugs that are "sparingly liquisolid compacts patents and trademarks 1 part solute into 30 to parts of water"slightly water-soluble" 1 part solute into to parts of water"very slightly water-soluble" 1 part solute into to 10, parts of waterand "practically water-insoluble" or "insoluble" 1 part solute into 10, or more parts of wateras defined in USP XXII or Remington's Pharmaceutical Sciences.
The term "liquisolid systems" refers to powdered forms of liquid medications formulated by converting liquid lipophilic drugs, or drug suspensions or solutions of water-insoluble solid drugs in suitable non-volatile solvent systems, into "dry" i.
Based on the type of liquid medication contained therein, liquisolid systems may be classified into three subgroups: The term "liquisolid compacts" refers to immediate or sustained release tablets or capsules that are prepared using the technique described under "liquisolid systems," combined with the inclusion of appropriate adjuvants required for tabletting or encapsulation, such as lubricants, and for immediate or sustained release action, such as disintegrants or binders, respectively.
The term "liquisolid Microsystems" refers to capsules prepared by the technique described under "liquisolid systems" combined with the inclusion of an additive, e. The term "plateau compressional force" is the force required to achieve maximum powder cohesiveness which, in turn, results in maximum tablet hardness. The term "carrier material" refers to a preferably porous material possessing sufficient absorption properties, such as microcrystalline and amorphous cellulose, which contributes in liquid absorption.
The term "coating material" refers to a material possessing fine and highly adsorptive particles, such as various types of amorphous silicon dioxide silicawhich contributes in covering the wet carrier particles and displaying liquisolid compacts patents and trademarks dry-looking powder by adsorbing any excess liquid.
These adsorptive particles have a particle size range of about 10 nm to 5, nm in diameter. Liquisolid systems are acceptably flowing and compressible powdered forms of liquid medications. A schematic outline of steps involved in the preparation of liquisolid systems liquisolid compacts patents and trademarks provided in FIG. As seen liquisolid compacts patents and trademarks, a liquid lipophilic drug e. On the other hand, if a solid water-insoluble drug e.
Inert, high boiling point, preferably water-miscible and not highly viscous organic solvent systems e. Next, a certain amount of the prepared drug solution or suspension, or the liquid drug itself, is incorporated into a specific quantity of carrier material which should be preferably of a porous nature and possessing sufficient absorption properties.
Materials with liquisolid compacts patents and trademarks porous surface and closely matted fibers in their interior, such as powder and granular grades of microcrystalline and amorphous cellulose, are most preferred as carriers. The resulting wet mixture is then converted into a dry-looking, nonadherent, free-flowing and readily compressible powder by the simple addition and mixing of a calculated amount of coating material.
Excipients possessing fine and highly adsorptive particles, such as various types of liquisolid compacts patents and trademarks silicon dioxide silicaare most suitable for this step. Before compression or encapsulation, various adjuvants such as lubricants and disintegrants immediate-release or binders sustained-release may be mixed with the finished liquisolid systems to produce liquisolid compacts tablets or capsules.
Based on the formulation technique used, liquisolid systems may be classified into two categories, namely, liquisolid compacts or liquisolid Microsystems. The first are prepared using the liquisolid compacts patents and trademarks outlined method to produce tablets or capsules, whereas the latter are based on a new concept which employs similar methodology combined with the inclusion of an additive, e. The advantage stemming from this new technique is that the resulting unit size of liquisolid microsystems may be as much as five times less than that of liquisolid compacts.
Regarding "powdered drug solutions," it must be emphasized that their preparation is not a solvent deposition technique since it does not involve drying or evaporation.
Since non-volatile solvents are used to prepare the drug solution or suspension, the liquid vehicle does not evaporate and thus, the drug is carried within the liquid system which in turn, is dispersed throughout the final product.
According to the proposed theories, the carrier and coating materials can retain only certain amounts of liquid while maintaining acceptable flow and compression properties. Depending on the excipient or carrier: Following are the major process steps and calculations involved in the formulation of acceptably liquisolid compacts patents and trademarks and compressible liquisolid compacts:. If a solid water-insoluble drug is formulated, the drug is first dissolved or suspended in a non-volatile solvent e.
The weight W in grams of drug solution or suspension or liquid drug required to be included in a single liquisolid compact unit possessing a desired strength of active ingredient is selected. The characteristic excipient or carrier: The desired excipient or carrier: If minimum unit dose weight U min is desired, the excipient ratio of the formulation must be selected to be equal to R min which is the characteristic minimum excipient ratio of the carrier: If a powder system carrier: Finally, the optimum quantities in grams of carrier Q o and coating q o materials required to be mixed with the desired amount W of liquid in order to produce an acceptably flowing and compressible liquisolid compact are determined using Equations 9 and 10, respectively.
The minimum carrier quantity Q min and maximum coating quantity q max required to produce an acceptably flowing and compressible liquisolid compact unit possessing minimum weight U min and containing an amount W of liquid may be assessed using Equations 11 and 12, respectively. It must be pointed out that, in terms of producing compacts of realistic unit size, the practical substance of the liquisolid formulation desired to be prepared may be assessed by predicting its unit dose weight U W using Equation This can be done as long as the weight W of the liquid medication to be included in a single liquisolid compact unit and the desired excipient ratio R of the formulation have been selected leading to the determination of the required optimum load factor L o.
The minimum possible unit dose weight U min which can be produced by the carrier: The formulation steps and mathematical expressions employed to calculate the optimum amounts of carrier and coating materials to produce acceptably flowing and compressible liquisolid systems have been compiled in Table 1.
The test is basically a titration-like procedure in which 25 to 30 grams of mixtures of the powders under investigation, with increasing amounts of a non-volatile liquisolid compacts patents and trademarks i. It should be noted that the non-volatile solvent used in the LSF test should be the one selected to be included in the liquid medication drug solution or drug suspension of the targeted liquisolid product; where a liquid drug is formulated, then the LSF test should be conducted with the liquid drug itself.
Preparing several powder systems each containing a carrier material and a coating material and selecting for each system a carrier: Assessing the flow rate and consistency of the admixtures thus obtained using a recording powder flowmeter and determining from this assessment the flowable liquid load factor.
Repeating steps b liquisolid compacts patents and trademarks c for the remaining powder systems of step a to determine the flowable liquid load factors of these systems; and. Plotting the flowable liquid load factors. The LSF test can be used not only for the preparation of acceptably flowing liquisolid compacts, but also for the general evaluation of the flowability of powders.
The above conditions were chosen based on results of preliminary work liquisolid compacts patents and trademarks that the powder flow of model formulations was satisfactory on a Zanasi LZ capsule machine Zanasi Co. Liquisolid compacts patents and trademarks selecting another machine, however, the limits of acceptable flowability should be liquisolid compacts patents and trademarks and adjusted to the requirements of that specific piece of equipment.
A test method, called the liquisolid compressibility LSC test, was developed and employed to determine the compressible liquid-retention potential, i. Basically, the method consists of the following steps:. Determining the compressible liquid-load factor. Repeating steps b through h for the remaining powder systems of step a to determine their compressible liquid load factors; and. Plotting the compressible liquid load factors thus obtained against the corresponding reciprocal carrier: The LSC test can be used not only for the preparation of acceptably compressible liquisolid compacts, but also for the general evaluation of the compactibility of powder excipients and formulations.
Compared to current methods of "compaction simulation," the LSC test is simple, accurate and reproducible. Determined physical properties of powder excipients, i. A great number of slightly and very slightly water-soluble and practically water-insoluble liquid and solid drugs, such as those previously mentioned, can be formulated into liquisolid systems using the new formulation-mathematical model.
It is well established that better availability of an orally administered water-insoluble drug is achieved when the drug is in solution form. That is why soft gelatin capsules containing solubilized forms of such medications demonstrate higher bioavailability compared to conventional oral solid dosage forms. The same principle governs the mechanism of drug delivery from liquisolid systems, specifically, powdered drug solutions, and is chiefly responsible for the improved dissolution profiles exhibited by these preparations.
In this instance, even though the drug is in a tabletted or encapsulated dosage form, it is held in a solubilized liquid state, which consequently contributes to increased drug wetting properties, thereby enhancing drug dissolution. Another advantage of liquisolid systems is liquisolid compacts patents and trademarks their production cost is lower than that of soft gelatin capsules because the production of liquisolid systems is similar to that of conventional tablets.
Still another possible advantage of liquisolid systems, particularly for powdered liquid drugs, should be mentioned. During dissolution of a liquisolid tablet, after the disintegration process is completed, the liquisolid compacts patents and trademarks solution or liquid drug, carried on the suspended and thoroughly agitated primary particles, is dispersed throughout the volume of the dissolution medium; such a phenomenon does not extensively occur during the dissolution process of soft gelatin capsule preparations.
Therefore, since more drug surface is exposed to the dissolving medium, liquisolid systems exhibit enhanced drug release. Most liquid or solid "water-insoluble drugs" may be formulated into immediate-release or sustained-release "liquisolid compacts" or "liquisolid Microsystems. Optimized immediate-release liquisolid tablets or capsules of water-insoluble drugs exhibit enhanced in-vitro and in-vivo drug release as compared liquisolid compacts patents and trademarks their commercial counterparts, including soft gelatin capsule preparations, as illustrated in FIGS.
Optimized sustained-release liquisolid tablets or capsules of water-insoluble drugs exhibit surprisingly constant dissolution rates zero-order release comparable only to expensive commercial preparations that combine osmotic pump technology and laser-drilled tablets, as illustrated in FIG.
The validity and applicability of the new mathematical model were tested by producing flowable and compressible systems containing various liquid medications. Liquisolid tablet formulations of the oily liquid drug, clofibrate, and of several water-insoluble solid drugs such as nifedipine, gemfibrozil, hydrocortisone, prednisolone, prednisone, spironolactone, methylclothiazide, and hydrochlorothiazide dissolved in suitable non-volatile solvents, were evaluated.
Additionally, the in-vitro dissolution profiles of such liquisolid products were compared with those of their commercial counterparts. Furthermore, the effects of aging on the crushing strengths and dissolution profiles of prepared liquisolid tablets were also investigated.
Finally, in-vivo studies were conducted in rats liquisolid compacts patents and trademarks compare clofibrate, nifedipine and gemfibrozil liquisolid compacts with their commercial counterparts. The following materials were used as received: The following commercially available products liquisolid compacts patents and trademarks used for the purpose of drug dissolution profile comparisons with liquisolid tablet formulations: Major pharmacological and physicochemical properties 10 of the active ingredients used are briefly discussed below:.
It is very slightly soluble in water and ether, slightly soluble in chloroform; 1 gram of drug is liquisolid compacts patents and trademarks in 40 ml of alcohol. It is very slightly soluble in water; 1 gram of drug is soluble in 30 ml of alcohol and in ml of chloroform. It liquisolid compacts patents and trademarks very slightly soluble in water; 1 gram of drug is soluble in ml of alcohol and in ml of chloroform.
