Untitled record

Fexofenadine Microcapsules and Compositions Containing Them

Full description

Background of the invention

Widely used dosage forms for oral administration include tablets and capsules. However, these dosage forms have several drawbacks. For example, it has been estimated that 50% of the population has trouble swallowing tablets (see Seager, 50 J. Pharmacol. and Pharm. 375-382 (1998). In particular, It may be difficult for some elderly people to swallow tablets or capsules, or to treat children who are unable or unwilling to swallow tablets or capsules. This leads to a poor recovery rate, and therefore has a negative impact on the effectiveness of the treatment.

The bitter taste of many active ingredients also makes it difficult to spray drugs on food, which is a common method used to administer treatment to children. Bitter-tasting drugs contained in chewable tablets are often coated with water-insoluble polymers, such as ethylcellulose, to mask the taste of the drugs by resisting breakage of the coated drug during tablet compression and/or chewable as well as simultaneous leakage of the active ingredient. Pungent taste. Accordingly, the total release of the drug from the chewable tablets into the gastrointestinal tract can take 2 hours or more. Recently, dosage forms have been given for an oral disintegrate tablet (ODT), which dissolves or disintegrates quickly in the buccal cavity and can therefore be taken without water.

Other suitable oral dosage forms include sachets and fine particle dispersions. These medications are suitable, especially for the elderly and children.

Fexofenadine hydrochloride Fexofenadine hydrochloride is a histamine H1 receptor antagonist, approved for the treatment of seasonal allergic rhinitis and chronic spontaneous urticaria. However, the formulation of fexofenadine is complicated by its low solubility in low pH (i.e., gastric) conditions. A typical method for low solubility is to formulate the drug as an ODT (a tablet that disintegrates when administered orally). However, this method is complicated by using fexofenadine hydrochloride, which has a pungent taste.

US Patent No. 6,723,348 describes the preparation of an orally dispersible (ODT) tablet containing fexofenadine in the form of fexofenadine that has been granulated using additional excipients, then coating the granules in a fluidized bed using a polymer coating. However, the manufacturing process is relatively complex and requires multiple granulation, packaging and mixing steps.

The object of the present invention is to provide fexofenadine in microcapsule form, using a simple process, in an immediate-release form whose taste has been masked.

General description of the invention

Detailed description:

All documents contained herein are included by reference for all purposes.

As used herein, the expression "coating weight" refers to the dry weight of the microcapsule shell divided by the weight of the microcapsule as a whole, multiplied by 100. For example, a coating weight of 20% means that in the given microcapsule, the coating represents 20% Of the weight of the microcapsule.

As used herein, the expression “average shell weight” refers to the average shell weight value for a batch of microcapsules. For example, if half of the microcapsules in a batch have a shell weight of 10% and the other half have a shell weight of 20%, then the average shell weight of the given batch of microcapsules is 15%.

As used herein, the term “microcapsules” refers to a drug (e.g., fexofenadine or its salt, ester, and/or soluble form, or crystalline form thereof) encapsulated in a water-insoluble polymer shell.

As used herein, the term “microencapsulation” refers to the process of encapsulating a drug using a water-insoluble polymer.

As used herein unless otherwise noted, references to the expression “fexofenadine” mean the compound itself fexofenadine or its salt, ester, and/or soluble, or crystalline form thereof.

As used herein, the term “API” refers to a “pharmaceutical active ingredient,” such as fexofenadine or a salt, ester, and/or soluble thereof, or polymorph thereof.

The present invention provides microcapsules of fexofenadine, a pharmaceutical composition comprising taste-blurred immediate-release microcapsules and a water-soluble polymer shell. Fexofenadine microcapsules may be in the form of co-granulated microcapsules and may include additional active ingredients and excipients. In one embodiment of the present invention, fexofenadine is fexofenadine hydrochloride.

The fexofenadine of the present invention may be crystalline or amorphous or combinations thereof. Any crystalline forms of fexofenadine that can be used in the preparation of microcapsules, a microcapsule granule and co-granulated microcapsules of the present invention are included.

The water-soluble polymer of the present invention may be any suitable and pharmaceutically acceptable water-soluble polymer that forms a shell around fexofenadine particles, thus producing fexofenadine microcapsules exhibiting immediate and tasteless release properties. Examples of water-insoluble polymer that may be used in the present invention include ethylcellulose, polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, copolymers of ammonio-methacrylate and mixtures thereof. In one embodiment, the water-insoluble polymer of the invention is ethylcellulose.

The amount and type of polymer contained in the coating contributes to controlling the release of fexofenadine, making it possible to adjust the degree of masking and/or release of fexofenadine. In the present invention the coating polymer is insoluble in water. The average shell weight of the microcapsules of the present invention ranges from about 2% to about 40%, including about 5%, about 10%, about 13%, about 15%, about 17%, or about 18% , or about 20%, or about 25%, or about 30%, or about 35% or about 40%. Typically, the average shell weight of the microcapsules of the present invention ranges from about 10% to about 20%. More typically, the average shell weight of the microcapsules of the present invention ranges from about 13% to about 18%. In one embodiment of the present invention, the microcapsules have an average shell weight of about 15%.

The wettability of the water-insoluble shell of microcapsules can be improved by treatment with surfactants. A surfactant layer can be applied to microcapsules by suspending them in a solution containing the surfactant, or by a fluid coating process. The surfactant solution contains at least one surfactant and optionally other components such as a lubricant or anti-viscosity agent. The surfactant should be soluble in a solvent in which the coating polymer is practically insoluble under the relevant conditions, e.g., at room temperature. Suitable surfactants include sodium docusate (DOSS), odium lauryl sulfate, fatty acid ester, Tween, Lutrol F68, sorbitan oleate, sorbitan laurate etc.

Other wetting agents can be chosen from: hydroxypropyl cellulose, polyethylene glycol 600, 1000, 3350 and 6000. In one embodiment, the surfactant in one case is approximately 10 w/w%.

Typically, the surfactant concentration ranges from about 0.25 w/w% and about 2 w/w%, or between 0.5 w/w% and about 1.5 w/w%, or between 0.45 w/w% and 0.75 w/w%. In one embodiment, the surfactant concentration in solution is about 0.45, in another it is about 0.6 w/w%, in another it is about 0.75 w/w%, in another it is about 1 w/w%, and yet another embodiment About 1.5 w/w%. Methods for wetting are also described in US Patent No. 6,509,034. A special antiviscosity agent is silicon dioxide.

If necessary, one or more protective coating layers (e.g., Opadry Clear, etc.) may be applied to the microcapsules of the invention.

Another embodiment of the present invention is a fexofenadine microcapsule pellet coated with a water-insoluble polymer.

In the present invention at least 80% of the immediate-release masked fexofenadine microcapsules have a particle size distribution (PSD) of less than 500 microns; Preferably, the percentage of microcapsules with a PSD of less than 355 microns should not be less than 80%; Preferably, the percentage of microcapsules with a PSD of less than 250 microns should not be less than 80%. In one embodiment also the percentage of microcapsules having a PSD of less than 200 microns is not less than 80%. Immediate-release blinded microcapsules are also used to prepare immediate-release blinded microcapsules that are co-granulated.

Another embodiment is a co-granulation product of water-soluble encapsulated microcapsules and at least one inactive ingredient. Co-granulation products are obtained when microcapsules are granulated with a portion of at least one inactive ingredient. Inactive ingredients can for example be selected from the group consisting of sugar alcohol and saccharides, such as sucrose, xanthan gum, beta-cyclodextrin, xylitol, sorbitol, mannitol, lactose, arabitol, isomalt, glycerol, or alginate, microcrystalline cellulose, carboxymethylcellulose or mixtures thereof. Disintegrants in combination with sugar alcohols or saccharides may also be inactive ingredients suitable for addition to fexofenadine microcapsules or co-granulation products. The microcapsule co-granulation product disclosed herein comprises fexofenadine microcapsules having a water-insoluble shell and at least one inactive ingredient. Specific examples of microcapsule:inactive ingredient(s) ratios range from 3:1 to 10:1, from 5:1 to 8:1, and from 6:1 or 7:1.

The fexofenadine microcapsule co-granulation product of the invention has a dissolution rate comparable to that of wet microcapsules. In one embodiment the particle size of the combined granulation product is preferably less than 600 µm with a reduced amount of granulation less than 125 µm. The reduced amount of the fine fraction is appropriate because this fraction consists almost entirely of non-granulated microcapsules and the presence of high levels of this fraction can be linked to the low homogeneity of the co-granulation product.

In one embodiment the co-granulation product has the following characteristics: a ratio of 7:1; Homogeneity difference <5.0%; Fine fraction <125µm <5.0%; Fraction above 600 μM <10.0%; Process yield is about 97.0%. Another special embodiment of the invention is that the products of co-granulation have the following properties: a ratio of 7:1; Homogeneity difference <5.0%; Fine fraction <125µm <5.0%; Fraction above 600 μM <5.0%; Process yield is about 97.0%.

Another embodiment of the present invention is a combination of a co-granulation product of a fexofenadine microcapsule and a co-granulation product of at least one inactive ingredient. The inactive ingredient granulation product comprises one or more inactive ingredients, which may for example be selected from the group consisting of sugar alcohol and saccharides, such as sucrose, xanthan gum, beta-cyclodextrin, xylitol, sorbitol, mannitol, or lactose, arabitol, isomalt, glycerol, alginate, microcrystalline cellulose, carboxymethylcellulose or mixtures thereof. Disintegrants in combination with sugar alcohols or saccharides may also be inactive ingredients suitable for addition to co-granulation products. The mixture (also called a bulk mixture) should preferably have a ratio of co-granulated microcapsules to the inactive ingredient(s) that have been granulated of 1:1. The co-granulated product comprises a fexofenadine microcapsule, sucrose and xanthan gum, and the co-granulated active ingredient comprises sucrose

Another embodiment of the present invention is a pharmaceutical composition comprising taste-masked fexofenadine microcapsules coated with a water-insoluble polymer. This composition includes fexofenadine microcapsules as well as at least one inactive ingredient which can be granulated or granulated and/or at least one excipient.

In one embodiment of the invention the pharmaceutical composition of the invention comprises a co-granulated product of a fexofenadine microcapsule that has been blended with at least one inactive ingredient which can be either granulated or non-granulated. An embodiment of the invention is whether the pharmaceutical composition has microcapsule co-granulation products and at least one granulated inactive ingredient in a 1:1 ratio.

The pharmaceutical compositions of the present invention provide immediate release of the active ingredient, for example, fexofenadine hydrochloride. In one embodiment, the compositions of the present invention release at least about 60% of fexofenadine hydrochloride within 15 minutes into a second JP fluid at pH 6.8 (JapanesePharmacopeia). In another embodiment, the compositions of the present invention release at least about 65% of the fexofenadine hydrochloride within 15 minutes into a second JP fluid at pH 6.8. In another embodiment, the compositions of the present invention release at least about 70% of the fexofenadine hydrochloride within 15 minutes into a second JP fluid at pH 6.8. In yet another embodiment, the compositions of the present invention release at least about 75% of the fexofenadine hydrochloride within 15 minutes into a second JP fluid at pH 6.8. In yet another embodiment, the compositions of the present invention release at least about 80% of the fexofenadine hydrochloride within 15 minutes into a second JP fluid at pH 6.8. In yet another embodiment, the compositions of the present invention release at least about 85% of the fexofenadine hydrochloride within 15 minutes into a second JP fluid at pH 6.8. In another embodiment, the compositions of the present invention release at least about 90% of the fexofenadine hydrochloride within 15 minutes into a second JP fluid at pH 6.8. In another embodiment, the compositions of the present invention release at least about 95% of the fexofenadine hydrochloride within 15 minutes into a second JP fluid at pH 6.8.

In another embodiment, the compositions described above may be combined with at least one additional pharmaceutical excipient. Excipients used in the compositions or dosage forms of the present invention include fillers, diluents, lubricants, disintegrants, binders, lubricants, etc. Other pharmaceutically acceptable excipients include acid-converting agents, alkali-converting agents, preservatives, antioxidants, buffering agents, hook compounds, coloring agents, complexing agents, emulsifying and/or solubilizing agents, flavoring and flavoring agents, humectants, Desalination, wetting agents, etc.

Examples of fillers, diluents and/or binders include, but are not limited to, lactose (e.g., spray-dried lactose, α-lactose, β-lactose, Tabletose, various grades of Pharmatose, Microtose or Fast-Floc), microcrystalline cellulose (e.g., Avicel PH101, Avicel PH102, Ceolus KG-802, Ceolus KG-1000, Prosolv SMCC 50 or SMCC90, and various brands of Elcema, Vivacel, Ming Tai or Solka-Floc), hydroxypropyl cellulose , L-hydroxypropyl cellulose (low substitution), hydroxypropyl methylcellulose (HPMC) (e.g., Methocel E, F and K, of Metolose SH supplied by Shin-Etsu, Ltd., e.g., 4000 cP grades of Methocel E and Metolose 60 SH, 4000 cP grades of Methocel F and Metolose 65 SH , 4000, 10,000 and 15,000 cP grades of Methocel K; 4,000, 15,000, 39,000 and 100,000 cP grades of Metolose 90 SH), methylcellulose polymers (e.g., Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylhydroxyethylcellulose and other cellulose derivatives, sucrose, xanthan gum, cyclodextrin (e.g., beta-cyclodextrin), agarose, sorbitol, mannitol, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch rice starch) calcium phosphate:

Such as calcium calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, xanthan gum, beta- cyclodextrin etc.

Or combinations thereof. Specific examples of diluents include: for example, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, xanthan gum, beta-cyclodextrin, etc. or combinations thereof.

Specific examples of lubricants and lubricants include: for example, silicon dioxide, stearic acid, magnesium stearate, calcium stearate or other metallic stearates, talc, waxes and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils , corn starch, sodium stearyl fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate, sodium acetate etc.

Other excipients include, for example, flavoring agents, coloring agents, flavor masking agents, pH adjusting agents, regulating agents, preservatives, stabilizing agents, antioxidants, wetting agents, moisture adjusting agents, surfactants, Suspension agents, absorption enhancing agents, modified release agents, etc.

Non-specific examples of flavoring agents include, for example, cherry, orange, banana, strawberry or other acceptable fruit flavours, or mixtures of cherry, orange and other acceptable fruit flavours, up to, for example, about 3% based on tablet weight. In addition, the compositions of the present invention may also comprise one or more sweetening agents such as aspartame, sucralose, other pharmaceutically acceptable sweetening agents, or mixtures of said sweetening agents, up to about 2% by weight, based on the weight of the tablet . Furthermore, the compositions of the present invention can comprise one or more coloring agents FD and C, up to, for example, 0.5% by weight, on a tablet weight basis.

Antioxidants include, for example, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, etc.

The fexofenadine microcapsules or microcapsule co-granulation product of the invention can be formulated into a variety of final dosage forms including tablets (e.g., orally disintegrant, chewable, dispersible, soluble, effervescent), hard gelatin capsules Sprays, suspensions, seed bags for permanent or improvised suspensions, and seed bags for direct oral administration. The microcapsules or the microcapsule co-granulation product of the invention or a mixture thereof may be formulated into a dry syrup in the presence of suitable inactive ingredients and also possible excipients. The dry syrup preparation is a quick-dissolving powder that is formulated to be easy to swallow. It can be given directly as a powder, or diluted with a liquid, for example with 3-5 ml of water in a tablespoon or 15-50 ml of water in a cup. Methods for making syrup preparations are described in U.S. Patent Publication No. 2008/0064716, which is incorporated herein by reference.

The preferred dry syrup consists of a co-granulated product of a fexofenadine microcapsule whose flavor has been masked in a 1:1 ratio relative to the granulated inactive ingredients; The co-granulation product has the following properties: the microcapsule ratio is 7:1 to the inactive ingredient; The co-granulated products contain sucrose and xanthan gum, the co-granulated active ingredient includes sucrose. The dry fexofenadine syrup according to the present invention has normal chemical properties such as particle size, dissolution rate and taste masking that are minimally affected by the filling step. This dry syrup has a high homogeneity rate. In one embodiment of the invention the combined grain product has a homogeneity difference of <5.0%; Fine fraction <125µm <5.0%; Fraction above 600 μM <5.0%; Process yield is about 97.0%;

The dry powder is packed in a zipper bag or package with adhesive tape. The seed bag is selected according to the ability to accurately dispense the product, the lowest achievable filling weight, and the effect of mechanical pressure on granulation yield; To use different packing images. Any filling methods can be used for flat button bags and different filling weights. The specific filling weights are 300 and 600 mg, and are applied here in the preparation of very low dose strengths of the drug (15 and 30 mg). The final packaging can have many forms, such as a pack with adhesive tape or a zipper bag; An example of packaging could include five boxes in a row connected to each other using a thin layer of PE. The masked fexofenadine microcapsules of the present invention can be prepared using the clustering process, an effective technique for producing masked microcapsules. The clustering process involves precipitation of microcapsules with salt into liquid-like colloidal droplets rather than solid or gel-like agglomeration products. The clustering process may be performed as described in U.S. Patents Nos. 5,252,337, 5,639,475, 6,139,865 and 6,495,160 the contents of which are expressly incorporated herein by reference for all purposes.

The microcapsules of the present invention may be prepared by providing a homogeneous solution of the water-insoluble polymer in a suitable solvent in which the active ingredient is dispersed, and by selecting the coating additives in suspension. Phase separation can therefore be used to cause insolubility of the water-insoluble polymer, which gels (complexion products) around the active ingredient particles to form microcapsules. Length separation can be accomplished, for example, by a difference in temperature or pH or by adding a phase separation inducing agent to the organic solvent (i.e., a phase-inducing agent) that causes the insoluble polymer to become insoluble in water. Finally, the obtained microcapsules are subjected, if necessary, and extracted.

In particular, the process of preparing taste-masked immediate-release particles according to the present invention comprises the following steps: (a) dissolving the water-insoluble polymer in an organic solvent; (b) Suspension of fexofenadine in organic solvent; (c) applying a water-insoluble polymer coating to fexofenadine by phase separation; (d) separation of microcapsules from said organic solvent, for example by filtration, centrifugation; and (e) removal of the remaining organic solvent by drying the microcapsules.

As discussed above, the phase separation step can be performed by a difference in temperature or pH, or by adding a phase inducing agent to the organic solvent that causes the waterless polymer to become insoluble. In one embodiment, the phase separation step is performed by adding a phase inducing agent to the organic solvent. Examples of suitable phase inducing agents that may be used in the present invention include polyethylene, polyisobutylene, butyl rubber, polybutadiene, isoprene methacrylic polymers, organosilicon polymers, organic polymers such as polydimethyl siloxane, paraffin, etc. In one embodiment, the phase inducing agent is polyethylene.

The organic solvent can be a single organic solvent or a mixture of organic solvents. According to the clustering process, the organic solvent is chosen to dissolve the coating polymer, but not the active component. Suitable organic solvents include cyclohexane or other hydrocarbon solvents. In one embodiment, the organic solvent is cyclohexane.

Non-specific examples of water-insoluble polymers include ethylcellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, neutral methacrylic acid-methylmethacrylate copolymers, copolymers. preparing taste-masked immediate release particles according to the present invention, neutral polymer is ethylcellulose, the phase polyethylene, the solvent is cyclohexane and the fexofenadine is fexofenadine hydrochloride..

In one embodiment of the process for preparing flavored immediate-release particles, the water-insoluble polymer is ethylcellulose, the phase inducing agent is polyethylene, the solvent is cyclohexane and the fexofenadine is fexofenadine hydrochloride. Fexofenadine microcapsule co-granulation products whose taste has been masked are prepared by microcapsule co-granulation (prepared by the method described above) with an inactive ingredient (e.g., sugar alcohol and/or saccharides) as a fine powder in a fluid bed by spraying a binder solution. The process includes the following steps: (1) microencapsulation of fexofenadine; (2) Selective hydration of microcapsules; (3) addition of hydrated or non-hydrated fexofenadine microcapsules to inactive ingredient(s); (4) Spraying the binder solution; (5) drying of granules; and (6) sifting the granules.

The granulation process can be carried out in a conventional granulation unit according to traditional techniques. The binder solution consists of one or more inactive ingredients, preferably two inactive ingredients; This is suitable for effective granulation of the microcapsule with sucrose. The binder solution should preferably consist of sucrose and xanthan gum. Other inactive ingredients may be selected from the group consisting of sugars, sugar alcohols, saccharides, sugar/sugar alcohol combinations and disintegrants. The following variables are kept under control during this process: the amount of binder solution, the ratio between the microcapsules and the inactive ingredient(s); Spray rate of binder solution; Ablation pressure; air flow. Granule drying is performed under the same controlled conditions of inlet air temperature, inlet air flow, etc. The granules are sieved using a stainless steel mesh of 840 micrometres.

The combined granulation product is then mixed with the granulation product of the inactive ingredient(s). The final mixture includes the co-granulation product mentioned above and the granulation product of the inactive ingredient(s). In a particular embodiment, this pharmaceutical composition has a ratio of co-granulation product and inactive ingredient(s) of 1:1.

Certain inactive ingredient(s) consist of sucrose. The granulation product is obtained by a process comprising the following steps: (1) addition of the inactive ingredient(s); (2) Spraying the binder solution; (3) drying of granules; (4) Sieving and calibration. During this process the following test conditions are controlled: the amount of powder granulated; Solution spray rate; pressure ablation; and inlet air humidity. Air flow is maintained constant. All drying steps are performed under the same conditions (inlet air temperature, inlet air flow), etc. The granules are sieved using a 600 micrometer or 840 micrometer stainless steel mesh. Granules larger than 840 micrometers are pushed past a 600 micrometer mesh granulator. The co-granulation product, granulated inactive ingredient(s), is mixed with additional ingredients (e.g. flavoring, lubricants) under controlled rotation speed for an appropriate mixing time.

The process of preparing fexofenadine dry syrup includes the following various steps: (1) microencapsulation of fexofenadine; (2) Selective hydration of microcapsules; (3) co-granulation of wet or non-wet microcapsules with at least one inactive ingredient (e.g. sucrose); (4) separate granulation of the inactive ingredient(s) (e.g. sucrose); (5) Mix the fexofenadine co-granulation product obtained from step (3) with the inactive ingredient(s) that were granulated (such as sucrose) obtained from step (4) and with other additional ingredients (such as flavorings and silicon dioxide (6) block mixture filling Of dry fexofenadine syrup for step (5) in seed bags. The present invention also provides a method for treating an inflammation-related condition in an individual. The method comprises administering to an individual a needed pharmaceutical composition comprising immediate-release masked microcapsules, wherein the microcapsules comprise fexofenadine and a water-insoluble polymer shell. Inflammation-related conditions include seasonal allergic rhinitis and chronic spontaneous urticaria.

The dose of fexofenadine hydrochloride that is given for suppositories can vary based on the age of the individual being treated as well as the symptoms. General doses for fexofenadine hydrochloride are 15 mg twice daily, 30 mg twice daily, 60 mg twice daily, and 180 mg once daily. Accordingly, the dosage form prepared using the compositions of the present invention can comprise, for example, 15 mg of fexofenadine hydrochloride, 30 mg of fexofenadine hydrochloride, 60 mg of fexofenadine hydrochloride or 180 mg of fexofenadine hydrochloride.

The following examples are provided for the purpose of illustration, and should not be considered a limitation of the invention.

Brief explanation of the drawings

Figure 1: Photographic micrographs of fexofenadine microcapsules in cyclohexane, sample 1 (average weight ethylcellulose 10%).

Figure 2: Photographic micrographs of fexofenadine microcapsules in cyclohexane, sample 2 (average weight ethylcellulose 13%).

Figure 3: Photographic micrographs of fexofenadine microcapsules in cyclohexane, sample 3 (average weight ethylcellulose 15%).

Figure 4: Photographic micrographs of fexofenadine microcapsules in cyclohexane, sample 5 (average weight ethylcellulose 17%).

Figure 5: Photographic micrographs of fexofenadine microcapsules in cyclohexane, sample 6 (average weight ethylcellulose 20%).

Figure 6: A photographic micrograph of a microcapsule, sample 4 15% ethylcellulose (2.5x magnification).

Figure 7: A photographic micrograph of a microcapsule, sample 7 20% ethylcellulose (2.5x magnification).

Figure 8: Particle size distribution (PSD) of microcapsules using 15% ethylcellulose.

Figure 9: Forms of fexofenadine microcapsules, ethylcellulose 15%, in JP buffer solution at pH 6.8 (n = 6).

Figure 10: Dissolution patterns of fexofenadine microcapsules, with or without the addition of 0.5 ml of 0.01 M DOSS in the dissolution medium.

Figure 11: Dissolution profiles of fexofenadine from artificially hydrated microcapsules of JP fluid at pH 6.8 (n = 6).

Figure 12: Dissolution rate of fexofenadine from microcapsules using three different levels of average volume of ethylcellulose.

Figure 13: Dissolution profiles of a second JP liquid at pH 6.8 for wettable microcapsules at three different levels of average volume of ethylcellulose.

Figure 14: Forms of fexofenadine dissolution in different dissolution media.

Figure 15: Particle size analysis of SG granulation product (sample 68), selected fraction size ranging from 60-250 micrometers.

Figure 16: Particle size analysis of the SGX granulation product (sample 68), a selected fraction ranging in size from 60-250 micrometers.

Figure 17: Particle size analysis of the SbCD granulation product (sample 68), a selected fraction ranging in size from 60-250 micrometers.

Figure 18: The dissolution rate of fexofenadine from microcapsules containing 13% of the average weight of ethylcellulose.

Figure 19: The dissolution rate of fexofenadine from preparations consisting of microcapsules containing 17% of the average weight of ethylcellulose.

Figure 20: Dissolution rate of fexofenadine from simple microcapsules formulated with 20% of the average weight of ethylcellulose.

Figure 21: Dissolution profiles (of a second JP fluid) at pH 6.8 for capsules containing 13% ethylcellulose (sample 8) and the corresponding prototypes sample 36-sample 32.

Figure 22: Dissolution profiles (of a second JP fluid) at pH 6.8 for capsules containing 17% ethylcellulose (Sample 9-D) and the corresponding prototypes Sample 39 - Sample 33.

Figure 23: Dissolution profiles (of a second JP fluid) at pH 6.8 for capsules containing 20% ethylcellulose (sample 6-D2) and the corresponding prototype sample 38.

Figure 24: A dissolution rate of 13% of the average weight of the microcapsule shell (sample 8) in different dissolution media.

Figure 25: Dissolution rates for a formulated product containing microcapsules containing 13% average weight of ethylcellulose (sample 32) in different dissolution media.

Figure 26: Dissolution rates of 17% of the average weight of microcapsule shells (sample 9-D) in different dissolution media.

Figure 27: Dissolution rates for a formulated product containing microcapsules containing 17% average weight of ethylcellulose (sample 33) in different dissolution media.

Figure 28: A radar graph showing the effect of process variables on the formation of small particles.

Experiments part:

1. Fexofenadine microcapsules:

1-1 Methods and equipment for preparing fexofenadine microcapsules

The cyclohexane was cast into a microencapsulation reactor. Then under continuous stirring, fexofenadine HCl, ethylcellulose (EC) and polyethylene were added.

The mixture was heated and then cooled. Microcapsules were extracted, washed (one or more times), filtered, and dried overnight (about 16 h) in a fume hood or hood at 40°C.

The powder was sieved through a sieve opening of 300 μm.

Table 1. List of sequential operations

Component

Step

hardware

Fexofenadine, Ethylcellulose, Epolene1, Cyclohexane2

Clustering using phase separation

Reactor

temperature control system,

Stirring unit

Washing

Filtration system

Purification

Filtration system

Drying

Cover, oven

Palm trees

sieve

1Removed during the washing step 2Removed during the drying step

Multiple batches of multiple capsules were prepared; The amount of ethylcellulose shell (w/w%, calculated as microcapsule weight increment) in the final microcapsules is summarized in Table 2.

Table 2. Average shell weight of microcapsules

Section

Casing weight (%)

Sample 1

10

Sample 2

13

Sample 3

15

Sample 4

15

Sample 5

17

Sample 6

20

Sample 7

20

Microcapsules are characterized by appearance, particle size distribution, residual solvent content and dissolution rate. Microscopic evaluation at the end of the microencapsulation process of five batches shows deposition of an appropriate polymer shell around the fexofenadine particles consistent with the amount of polymer used in the preparation of different batches (see Figures 1-5).

As shown in Figures 6 and 7, the increase in particle size and level of agglomeration of the microcapsules was found to be proportional to the amount of polymer shell that was applied. Fexofenadine granules undergo a process similar to granulation and form discrete fine aggregates in the size range of 50 to 200 microns; It is clear that the cluster size increases with the polymer level.

The particle size distribution of microcapsules (PSD) with a 15% shell (obtained from sample 3) is measured. A quantity of microcapsules ranging from 25 g to 50 g was poured into a 100 ml HDPE bottle, 0.2% (w/w) Syloid 244 (colloidal silicon dioxide, W.R. Grace, Columbia, Maryland) was sieved through meshes of 150 micrometers, added to microcapsules and mixed manually for two minutes.

The mixture of microcapsules and Syloid 244 was sieved using a digital octagon for 10 minutes at an amplitude of 7. The results are shown in Figure 8. The fine fraction of microcapsules above 250 microns is not less than 80%.

Table 3. Test values for fexofenadine in microcapsule batches using different encapsulation levels

the sample

Test(mg/g)

existing

Theoretical

Sample 8

(13% average shell weight)

832.7

852.9

Sample 9-D

(17% average shell weight)

802.1

813.7

Sample 6-D2

(20% average weight of cover)

767.3

784.3

As shown in Table 3, the microcapsule test values are close to the theoretical values (98-99%). The amount of residual solvent (cyclohexane) is always less than 100 ppm for all microcapsules prepared in the laboratory.

1-2 Industrial standard for microencapsulation

Fexofenadine microcapsules are prepared at different ethylcellulose levels (15, 18 and 20%) by gelation in an 80-gallon stainless steel reactor and using a fluid bed apparatus for the drying step. Fexofenadine HCl (Code 1) and fexofenadine HCl (Code 2) are used in preparing microcapsules. Microcapsules containing 15% ethylcellulose (sample 71) are prepared; Sample 72 and Sample 73 are thawed “in the laboratory” (each prepared using a different initiator fexofenadine (code 2).

There were no significant differences between microcapsules prepared with different API batches (non-parametric Mann-Whitney statistical analysis, p=0.05).

Microcapsules with ethylcellulose levels of 15, 18 and 20% are obtained. Microencapsulation experiments are performed by placing the API and inactive ingredient(s) in an 80-gallon reactor, then adding fresh cyclohexane.

The temperature variables and stirring conditions were set as described above. At the end of the thermal cycle, the stirrer rotation is stopped and the product is left to settle. The supernatant is removed using a vacuum pump, and fresh solvent is added. The mixture is stirred for a short time. Later, the microcapsules are left to settle again and part of the cyclohexane is removed for a second time.

The microcapsules are then filtered in a supplied fluid bed equipped with a 70 µm stainless steel sieve at the bottom under an inert nitrogen atmosphere and under low pressure. After removing the solvent, the microcapsule slurry is dried in the same fluid bed to reach Residual cyclohexane level is less than 3000 ppm.

The obtained product is manually drained from the fluid bed chamber and sieved through an 840 micrometer stainless steel sieve.

Table 4. Microencapsule batch formulations.

Material (kg)

Sample 74

15% EC

Sample 75

15% EC

Sample 76

15% EC

Sample 77

15% EC

The fexofenadine

28.33

28.33

28.33

28.33

ethylcellulose

5.00

5.00

5.00

5.00

Washing

no

no

Yes

Yes

Experimental test (mg/g)

836.7

825.9

832.3

850.7

The dissolution profiles of fexofenadine microcapsules in a buffer solution of a second JP fluid pH 6.8 (15% ethylcellulose level) are shown in Figure 9.

1-2 Microcapsule dissolution test

Microcapsule prototypes resulted in improved wettability when a small amount of surfactant such as DOSS was added to the dissolution medium.

Dissolution tests on microcapsules are performed by adding a small amount of surfactants to the dissolution medium.

Figure 10 shows the dissolution profile of microcapsules with 15% EC (sample 4) with or without the addition of 0.5 ml of 0.01 M DOSS in the dissolution medium.

A comparison of dissolution rates for commercial Allegra tablet preparations using a USP stirrer is provided in Table 5.

Table 5. Dissolution of fexofenadine microcapsules and Allegra tablets

% of drug released (SD)

a sample

EC

5 minutes

15 minute

30 minute

45 minute

Sample 7

20٪

17 (1)

46 (4)

77 (6)

88 (2)

Sample 4

15٪

30 (1)

78 (2)

97 (1)

95 (2)

Sample 1

10٪

92 (1)

97 (1)

96 (1)

96 (1)

*Allegra tablets

79 (3)

96 (3)

98 (3)

98 (3)

*With or without addition of 0.5 ml of 0.01 M DOSS.

This comparison indicates that at 15% and 10% ethylcellulose levels, the solubility of encapsulated fexofenadine is similar to that of tablet preparations. Taste evaluation indicates that 15% of the packaging gives acceptable taste characteristics.

Dissolution values using a formal analytical dissolution method using pH 6.8 buffer solution (second dissolution testing fluid, JP15) and microcapsule batch tests are summarized in Tables 6-8.

Table 6. Test and dissolution rate of microcapsules with 15% EC

Test(mg/g)

pH 6.8 buffer solution of second JP + 0.5 ml of 0.01 M DOSS

Percentage of released drug released (SD)

a sample

Theoretical value

Analytical value

5 minutes

15 minute

30 minute

45 minute

Sample 4

850

848.0

30 (1)

78 (2)

97 (1)

95 (2)

Sample 10

850

840.6

31 (2)

74 (6)

94 (2)

96 (1)

Sample 11

850

843.7

38 (2)

85 (9)

98 (2)

98 (2)

Microcapsules containing 15% ethylcellulose (sample 71) were prepared and hydrated (by in situ process at laboratory scale, sample 71/A) and the dissolution was compared in Table

Table 7. Test and dissolution rate of microcapsules with 17% EC

Test(mg/g)

pH 6.8 buffer solution of second JP + 0.5 ml of 0.01 M DOSS

Percentage of released drug released (SD)

Paid

Theoretical value

Analytical value

5 minutes

15 minute

30 minute

45 minute

Sample 12

830

824.7

22 (2)

56 (3)

83 (2)

92 (1)

Sample 13

830

826.7

23 (2)

58 (7)

82 (3)

91 (1)

Sample 9

830

815.3

23 (1)

55 (1)

85 (4)

93 (1)

1-4 Preparation of wet microcapsules

The hydrophilic nature of ethylcellulose results in some drawbacks when using microcapsules in an aqueous environment. When the final dosage form containing these microcapsules is placed in a glass of water, the hydrophobic microcapsules tend to float and contain agglomeration products (eg, clumps or clusters), and some tend to stick to the glass.

Enhanced wettability of microcapsules is achieved by treating the microcapsules with a minimal amount of surfactant (wetting treatment). Many different moisturizing ingredients have been investigated (eg sodium lauryl sulfate; sodium docusate; sucrose fatty acid ester; hydroxypropylcellulose and polyethylene glycol 600, 1000, 3350 and 6000, Lutrol F68 etc.).

Wet processing of microcapsules using surfactants is performed by suspending either the microcapsules in a surfactant solution, or by spraying the microcapsules with a surfactant solution using for example fluid bed encapsulation as described below or other suitable equipment. .

Suspension humidification process. The process is performed by suspending microcapsules (eg, sample 3, average shell weight 15%) in docusate sodium (DOSS) solutions diluted in cyclohexane. The suspension is mixed for about 15 minutes at 200 rpm, then Syloid 244 is added to the mixture while stirring.

The microcapsules are extracted by filtration using a standard apparatus. The microcapsules are then dried at room temperature for about 16 hours and sieved using a 300 micron sieve. The DOSS solution added to the microcapsules should preferably consist of no more than 0.25% DOSS. The following fractions were prepared: sample 8 (average shell weight 13%), sample 19-D (average shell weight 15%), sample 9-D (average shell weight 17%) and sample 6-D (average shell weight 20%).

Humidification process using a fluid layer. The process is performed using a fluid bed encapsulator equipped with a Wurster Insert, microcapsule shell and surfactant solution according to standard spraying procedures.

The treated microcapsules were then sieved through a 300-micron sieve. A 20-d sample was prepared, having an average EC volume of 15%. The microcapsules obtained are easily suspendable in an aqueous environment without causing agglomeration and water repulsion. Wet process recoverability is verified by dissolution test. Verification of “in vitro” dissolution values and analysis of impurities in microcapsule batches are described in the next section.

Laboratory-scale wet processing. Wetting is performed in a fluid bed sprayer by applying an aqueous solution of sodium docusate dispersed in silicon dioxide.

Three levels of surfactants: 0.45, 0.60 and 0.75%, were applied to 400 g sample 78 microcapsules (15% EC). The results obtained are shown in Table 8.

Table 8. “In vitro” dissolution values and drug analysis for different batches.

Paid

Docusate Na(%)

silicon dioxide(%)

fexofenadine (mg/g)

Buffer DRT solution, pH 6.8, of a second JP fluid

5 minutes

10 minutes

15 minute

30 minute

45 minute

Sample 14

0.75٪

2.25٪

824.5

822

952

941

951

941

Sample 15

0.60٪

2.27٪

825.7

841

942

941

941

931

Sample 16

0.45٪

2.27٪

826.8

762

911

931

931

931

Humidification treatment on an industrial scale. The industrial-scale wet curing process is performed using an 18-inch fluid bed apparatus, and batches of sample 17 and sample 18 microcapsules are obtained. The wet dispersion is applied to the fluid bed using a Watson-Marlow pump equipped with a Marprene tube. The theoretical composition is shown in Table 9 and the dissolution forms are shown in Table 10 and Figure 11, respectively. In addition, the water content (Karl Fisher analysis) of sample 18 (0.38%) was measured.

Table 9. Theoretical composition of microcapsules.

Paid

Fexofenadine microcapsule (%)

Docusate (%)

silicon dioxide(%)

Drug analysis (mg/g)

DOSS

Test(mg/g)

Sample 17

Sample 78 (15% cover) 97.13

0.60

2.27

805.23.3

5.90.1

Sample 18

Sample 78 (15% cover) 97.13

0.60

2.27

819.71.8

5.70.2

Table 10. Melting values of industrial wet microcapsules “in the laboratory”.

Values in a buffer solution of pH 6.8 for a second JP fluid

Paid

5 minutes

10 minutes

15 minute

30 minute

45 minute

60 minute

Sample 17

663

902

941

951

941

941

Sample 18

691

902

931

940

940

941

1-5 Analysis and testing of the dissolution of wet microcapsules

Impurities in different samples were analyzed.

Table 11. Total impurities in wet microcapsules prepared using different amounts of EC

a sample

Impurities (%)

MDL

102، 038

unknown

Overall

Sample 8 (13% cover)

0.03

0.05

0.08

Sample 9-D (17% cover)

0.03

0.04

0.07

Sample 6-D2 (20% cover)

0.04

0.05

0.09

As shown in Table 11, the wet microcapsule test values are close to the theoretical values (98-99%) and the total level of impurities is less than 0.1% for all samples tested.

Wet microcapsules are dissolved using a second JP fluid, pH 6.8. The results are summarized in the following Table 12 and some of them are also illustrated in the graph in Figure 12.

Table 12. Percentage release of fexofenadine from wet microcapsules at multiple time points for four levels of ethylcellulose

a sample

% drug release (SD) n=3

Zero minutes

5 minutes

15 minute

30 minute

45 minute

Sample 8 (13% coating)

0

59 (4)

97 (4)

98 (1)

97 (1)

Sample 19-D (15% coating)

0

44 (2)

90 (3)

97 (1)

96 (1)

Sample 9-D (17% coating)

0

34 (3)

83 (5)

97 (2)

97 (1)

Sample 6-D2 (20% coating)

0

24 (1)

62 (3)

89 (1)

97 (1)

-20-D sample (15% coating)

0

81 (4)

95 (2)

95 (2)

95 (2)

Samples with average shell weight levels of 13%, 15% and 17% had a fexofenadine release rate of 80% at 15 minutes. The dissolution rate is consistent with the EC level; That is, samples with higher coating levels show a lower dissolution rate, while samples with lower coating levels show a faster release rate. Of note, a batch treated with a surfactant applied with a fluid layer (20-D sample) has a faster release rate (80% release within 5 minutes) (see also Figure 13).

Wet microcapsule batch tests and their “in vitro” dissolution values are summarized in Tables 13-20.

Table 13. Testing of microcapsules with 13% EC using hydration treatment

Test(mg/g)

a sample

Theoretical value

Analytical value

Sample 21-D

852.9

826.2

Sample 22-D

852.9

826.0

Sample 23-D

852.9

832.7

Table 14. Testing of microcapsules with 15% EC using hydration treatment

Test(mg/g)

a sample

Theoretical value

Analytical value

Sample 24-D

833.3

nothing

Sample 11-D

833.3

828.9

Sample 25-D1

833.3

nothing

Sample 26-D1

833.3

nothing

Table 15. Testing of microcapsules with 17% EC using hydration treatment

Test(mg/g)

a sample

Theoretical value

Analytical value

Sample 12 d

813.7

799.6

Sample 13-D

813.7

805.1

Sample 9-D

813.7

802.1

Table 16. Testing of microcapsules with 20% EC using hydration treatment

Test(mg/g)

a sample

Theoretical value

Analytical value

Sample 6-D2

784.3

767.3

Sample 27-D

784.3

nothing

Table 17. Dissolution values of “in vitro” microcapsules with 13% EC using hydration treatment

Buffer solution, pH 6.8, of a second JP fluid. No surfactant added

Drug released (SD) n=3

a sample

5 minutes

15 minute

30 minute

45 minute

Sample 21-D

60 (3)

95 (1)

96 (2)

95 (1)

Sample 22 d

55 (5)

95 (1)

96 (1)

96 (1)

Table 18. Dissolution values of “in vitro” microcapsules with 15% EC using hydration treatment

Buffer solution, pH 6.8, of a second JP fluid. No surfactant added. Drug released (SD) n=3

a sample

5 minutes

15 minute

30 minute

45 minute

Sample 24-D

52 (1)

95 (1)

98 (1)

98 (1)

Sample 11-D

47 (2)

93 (3)

97 (1)

97 (1)

Sample 25-D1

51 (4)

92 (2)

96 (1)

95 (1)

Sample 26-D1

44 (2)

90 (3)

97 (1)

96 (1)

Table 19. Dissolution values of “in vitro” microcapsules with 17% EC using hydration treatment

Buffer solution, pH 6.8, of a second JP fluid. No surfactant added

Drug released (SD) n=3

a sample

5 minutes

15 minute

30 minute

45 minute

Sample 12-D

30 (2)

77 (7)

98 (2)

99 (1)

Sample 13-D

33 (2)

82 (3)

99 (2)

99 (1)

Table 20. Dissolution values of “in vitro” microcapsules with 17% EC using hydration treatment

Buffer solution, pH 6.8, of a second JP fluid. No surfactant added

Drug released (SD) n=3

a sample

5 minutes

15 minute

30 minute

45 minute

Sample 27-D

20 (1)

56 (2)

85 (1)

96 (1)

The "laboratory" solubility values agree with the amount of ethylcellulose applied. Batch-to-batch variation, within samples with the same coating level, is reduced due to the improved wettability and dispersion of the microcapsules. By comparing the dissolution profile of these wet microcapsules with the corresponding non-wet microcapsules, it was found that these wet microcapsules in a surfactant-free medium show a higher dissolution profile (Tables 21-24).

Table 21. “In vitro” dissolution values for microcapsules with 13% ethylcellulose with and without hydration treatment

a sample

Wet microcapsules

Add 0.5 mM of 0.01 M DOSS

Buffer solution, pH 6.8, of a second JP fluid

Percentage of released drug released (SD)

5 minutes

15 minute

30 minute

45 minute

Sample 21

no

Yes

50 (1)

94 (2)

97 (1)

96 (1)

Sample 21-D

Yes

no

60 (3)

95 (1)

96 (2)

95 (1)

Table 22. “In vitro” dissolution values for microcapsules with 15% ethylcellulose with and without hydration treatment

a sample

Wet microcapsules

Add 0.5 mM of 0.01 M DOSS

Buffer solution, pH 6.8, of a second JP fluid

Percentage of released drug released (SD)

5 minutes

15 minute

30 minute

45 minute

Sample 11

no

Yes

38 (2)

85 (9)

98 (2)

98 (2)

Sample 28-D

Yes

no

47 (2)

93 (3)

97 (1)

97 (1)

Table 23. “In vitro” dissolution values for microcapsules with 17% ethylcellulose with and without hydration treatment

a sample

Wet microcapsules

Add 0.5 mM of 0.01 M DOSS

Buffer solution, pH 6.8, of a second JP fluid

Percentage of released drug released (SD)

5 minutes

15 minute

30 minute

45 minute

Sample 12

no

Yes

22 (2)

56 (3)

83 (2)

92 (1)

Sample 12-D

Yes

no

30 (2)

77 (7)

98 (2)

99 (1)

Table 24. “In vitro” dissolution values for microcapsules with 20% ethylcellulose with and without hydration treatment

a sample

Wet microcapsules

Add 0.5 mM of 0.01 M DOSS

Buffer solution, pH 6.8, of a second JP fluid

% of drug released (SD)

5 minutes

15 minute

30 minute

45 minute

Sample 27

no

Yes

15 (1)

39 (3)

63 (4)

83 (6)

Sample 27-D

Yes

no

20 (1)

56 (2)

85 (1)

96 (1)

Wet microcapsules exhibit acceptable wettability and dispersibility in all media tested, without the need to add surfactant to the dissolution medium of the buffer solution. Figure 14 is a comparison of the dissolution profiles of fexofenadine microcapsules in different media with and without wetting treatment. From the above data it can be demonstrated that: small taste-masked microcapsules (about 200 micrometers) are easily dispersible in water; Furthermore, a suitable release form is achieved.

1-6 Analysis of residual solvent in batch microcapsules

The cyclohexane applied to wet and non-wet microcapsules is measured using different encapsulation levels at less than 100 ppm, based on the weight of the microcapsules. The data is summarized in Table 25:

Table 25. Residual solvent for wet and non-wet microcapsules prepared using different amounts of ethylcellulose

a sample

ethylcellulose

Moisturizing treatment

The remaining cyclohexane

Sample 12

17٪

no

21 ppm

Sample 12-D

17٪

Yes

15 ppm

Sample 11

15٪

no

26 ppm

Sample 11-D

15٪

Yes

17 ppm

Sample 6-D2

20٪

Yes

13 ppm

Sample 29

25٪

no

27 ppm

Sample 29-D

25٪

Yes

36 ppm

It is clear from the above that the remaining cyclohexane is considered to be within the ICH limits, as stated in the Q3C(R3) guideline.

2. Preparation of fexofenadine microcapsules that have been formulated

Fexofenadine microcapsules are formulated using a series of inactive ingredient(s) and/or excipient(s) to prepare and label prototype granules that: (1) are microcapsule compatible; (2) It also reduces the bitter taste of fexofenadine; (3) Microcapsules make it easy to swallow; (4) Makes microcapsules easy to dissipate in water; and/or (5) obtain microcapsules that are easily dispersed and suspended in water.

2-1 Select inactive ingredient(s).

The inactive ingredient(s) are selected and both paired combinations of fexofenadine and the inactive ingredient(s) are prepared and evaluated at drug to inactive ingredient(s) ratios and stored at 50°C, wet or dry in sealed glass vials. And leak-proof. At fixed times the chemical stability of the syntheses is evaluated using HPLC test. In general, the results indicate that the API with the selected inactive ingredient(s) is reasonably stable under standard temperature and humidity conditions. Various inactive component(s) are also used to evaluate the dispersal/suspension ability of the microcapsules (20 ml distilled water, 36 mg microcapsules), which are shown in Table 26.

Table 26. Visual evaluation of fexofenadine microcapsule suspension/dispersion in combination with different inactive ingredient(s).

Inactive ingredient(s).

Suspension quality

sucrose

good

xylitol

good

sorbitol

acceptable

mannitol

acceptable

Lactose monohydrate

good

MCC and sodium carboxymethylcellulose (CeolusRC-A591NF)

acceptable

b-cyclodextrin

good

Two formulation methods have been performed: direct mixing of fexofenadine microcapsules with a granulated product (excipients) and fluidized bed granulation of fexofenadine with a portion of sucrose to be further mixed with an additional amount of granulated sucrose to reach the final dilution.

2-2 Preparation and analysis of granulation products

Three types of granulation products were prepared by spraying the top of a fluid bed: (1) sugar granulation product (SG); (2) sucrose-xanthan gum (SXG) granulation product; and (3) the granulation product of sucrose- b -cyclodextrin (SbCD). The fluid bed granulation technique is chosen to obtain soft granules that have a uniform particle size and have the ability to dissolve quickly in water. SG is obtained by sucrose granulation using an aqueous solution of sucrose (5% w/w). The resulting product was dried and the granule fraction with size ranging from 250-600 μm was selected. The particle size and mass density (0.5 g/ml) of the resulting granules were characterized (Figure 15).

SXG is prepared by first granulating sucrose with an aqueous solution of sucrose (5% w/w) and then using a hydroalcoholic suspension of xanthan gum. The resulting product was dried and the pellet fraction ranging in size from 250-600 μm was selected. The particle size, mass density (0.5 g/mL) and residual ethanol content (< 100 ppm) of the resulting granulation product were characterized (Figure 16). SbCD is obtained by granulating a powder mixture of sucrose and b-cyclodextrin (1:2 w/w) with an aqueous solution of sucrose (5% w/w). The resulting product was dried and the pellet fraction ranging in size from 250-600 μm was selected. The particle size and mass density (0.4 g/mL) of the resulting product were evaluated (Figure 17).

The compositions of the three granulation products mentioned are described in Table 27.

Table 27. Theoretical composition of granulation products

SG

SGX

SbCD

sucrose

100.0٪

98.5٪

66.8٪

xanthan gum

-

1.5٪

-

b-cyclodextrin

-

-

33.2٪

2-3 Preparation of fexofenadine microcapsule/granulation product mixtures

2-3-1 The first set of examples of mixing fexofenadine microcapsule with granulation products SGX, SG and SBCD

Samples were prepared using fexofenadine HCl microcapsules at three different levels of average EC weight (13%, 17% and 20%). Each sample consists of a combined pellet of xanthan gum and sucrose (400 mg). In addition to these substances, each sample consists of a quantity of sucrose granules (150 mg) either alone or in combination with additional inactive ingredient(s), e.g., β-cyclodextrin (beta-CDX). The only exception here is for sample 39, which contains additional sucrose grains. Additional excipients were added in Sample 30, Sample 31, Sample 32, Sample 33 and Sample 34. Flavors were added to sample 30 and sample 31, while β-cyclodextrin (BCD) was added to sample 32, sample 33 and sample 34. A drug sample without active ingredients (sample 35) was also prepared. This sample consists of microencapsulated fexofenadine HCl instead of fexofenadine. Table 28 below summarizes the qualitative and quantitative compositions of payments.

Table 28. Batch combinations

Prototype of the buttoning bag <![if !supportLineBreakNewLine]>

Microcapsule

sucrose granules + xanthan gum (SGX)

sucrose granules (SG)

sucrose granule + BCD

(SBCD)

Sucrose granules + yogurt

Sucrose granules + strawberries

mg/bag of seed

Paid

EC%

Mg

Sample 32

Sample 23-D

13

36.0

400

150

586.0

Sample 36

Sample 23-D

13

36.0

400

150

586.0

Sample 39

Sample 9-D

17

37.4

400

437.4

Sample 33

Sample 9-D

17

37.4

400

150

587.4

Sample 37

Sample 9-D

17

37.4

400

150

587.4

Sample 35

U9A032_E36

A drug free of active ingredients

36.0

400

150

586.0

Sample 34

Sample 23-D

13

36.0

400

150

586.0

Sample 38

Sample 6-D2

20

38.5

400

150

588.5

Sample 30

Sample 6-D2

20

38.5

400

150

588.5

Sample 31

Sample 6-D2

20

38.5

400

150

588.5

The degree of homogeneity of the resulting granule dispersion is characterized before and after stirring in 20 ml of water.

In addition, parameters such as sedimentation/stability/flotation, resuspension capacity, residual material after decanting, and solubility are also evaluated at JP pH 6.8, 1 mM HCl (pH 3.0) and distilled water for the fexofenadine microcapsule/granulation mixture. .

The wettability and dispersibility test is performed in a 50 ml glass beaker using 20 ml of demineralized water at room temperature (20-25 °C). In particular, an amount of microcapsules corresponding to 30 mg of fexofenadine HCl and the selected inactive ingredient(s) are weighed and poured into the beaker. The mixture is stirred gently for 10 seconds and the tendency to form lumps, float, settle, and settle is observed for 30 seconds. Finally, the suspension is stirred again for two seconds and then poured, and the remaining material in the beaker is evaluated.

Finally, the mouthfeel and taste masking properties of the fexofenadine microcapsule/granule mixture are evaluated by placing the powder in the mouth or on a large spoon with a few milliliters of water. The maximum amount of inactive ingredient(s) and/or excipients added to fexofenadine microcapsule batches (@36 mg) is 550 mg.

2-3-1-1 Dissolution of fexofenadine microcapsule/granulation product mixtures

A series of tests were performed using fexofenadine microcapsules coated with an amount of ethylcellulose ranging from 13% to 20%, and mixed with three different types of granules, as described above in Table 28. Wetability/dispersibility experiments show that mixing granulation products with capsules Micronized fexofenadine does not have a negative effect on its wettability and dispersibility in water. Furthermore, serious dispersibility of formulations using a limited amount of liquid (1 tablespoon) has been demonstrated. Sample 35 is an active ingredient-free drug prepared using talc microcapsules instead of fexofenadine HCl. Sample 34 has the same composition as sample 32, and is prepared to confirm the taste masking ability of the microcapsules with a minimal level of encapsulation. All prototypes were prepared using pellets from SXG.

The SβCD granulation product was used in some samples (Sample 32, Sample 33, Sample 34) to evaluate the effect of the mentioned inactive ingredient(s) on reducing the sour taste. Sample 39 was prepared using a reduced amount of the inactive ingredient(s) to evaluate the effect of inactive ingredient(s) levels on mouthfeel. Prototypes of sample 30 and flavored sample 31 were also evaluated. The melting patterns of the samples are shown in the following tables and figures.

Taste masking tests indicate that all samples generate an immediate sweet sensation, followed by a somewhat sour sensation (after 20-30 seconds). However, this bitter taste has not been identified as annoying.

The dissolution results of the mixture of fexofenadine microcapsules/granulation products with 13%, 17%, 20% of the polymer obtained using a second JP fluid of pH 6.8 are summarized in Table 29-31 and are also illustrated in the graph in Figures 18, 19. 20. These results were compared to those obtained with microcapsules that were not formulated.

a sample

Percentage drug release (SD) n = 3

Zero minutes

5 minutes

15 minute

30 minute

45 minute

Sample 8 (microcapsules)

0

59 (4)

97 (4)

98 (1)

97 (1)

Sample 32

0

66 (2)

96 (1)

97 (1)

96 (1)

Sample 36

0

71 (2)

100 (1)

99 (1)

98 (1)

The dissolution properties of the products are similar to those of microcapsules with a slight increase in the total dissolution rate reported.

a sample

Percentage drug release (SD) n = 3

Zero minutes

5 minutes

15 minute

30 minute

45 minute

Sample 9-D (microcapsule)

0

34 (3)

83 (5)

97 (2)

97 (1)

Sample 33

0

37 (1)

84 (3)

96 (2)

95 (1)

Sample 37

0

44 (3)

90 (5)

97 (0)

96 (1)

Sample 39

0

49 (2)

93 (4)

97 (1)

96 (1)

The dissolution properties of the formulated products are similar to those of microcapsules with a slight increase in the total reported dissolution rate. The formulated product containing microcapsules with an average weight EC of 20% was dissolved with a second JP fluid pH 6.8. These results were compared to microcapsules that were not formulated. These results are summarized in Table 31 and are also illustrated in the graph in Figure 20.

a sample

Percentage drug release (SD) n = 3

Zero minutes

5 minutes

15 minute

30 minute

45 minute

Sample 6-D2 (microcapsule)

0

24 (1)

62 (3)

89 (1)

97 (0)

Sample 38

0

25 (1)

60 (4)

87 (5)

92 (1)

For each encapsulation level, the dissolution rate of the microcapsule prototypes formulated is similar to the dissolution rate of the microcapsules alone (see Figure 21-23). Obviously, the selected inactive ingredient(s) have no effect on the dissolution profile of the microcapsules. The dissolution rate of batches of product formulated with 13% microcapsules and 17% encapsulation and tested with 1 mM HCl was also determined; and DI water. The results are shown in the following tables, which also include the dissolution values in a second JP fluid, pH 6.8, as explained above, and are expressed graphically in Figures 24-27.

Table 32. Dissolution rate of microcapsules containing 13% of average weight of ethylcellulose (sample 8) in various dissolution media

Dissolution medium

Percentage drug release (SD) n = 3

Zero minutes

5 minutes

15 minute

30 minute

45 minute

JP has a second pH of 6.8

0

59 (4)

97 (4)

98 (1)

97 (1)

1 mM HCL (pH 3.0)

0

63 (1)

98 (1)

98 (0)

98 (1)

DI water

0

54 (4)

95 (1)

97 (1)

97 (1)

Table 33. Dissolution rate of fexofenadine microcapsule/pellet mixtures containing microcapsules with 13% average weight of ethylcellulose (sample 32) in various dissolution media

Dissolution medium

Percentage drug release (SD) n = 3

Zero minutes

5 minutes

15 minute

30 minute

45 minute

The second JP fluid has a pH of 6.8

0

66 (2)

96 (1)

97 (1)

96 (1)

1 mM HCL (pH 3.0)

0

77 (3)

98 (1)

97 (1)

97 (1)

DI water

0

57 (1)

90 (3)

92 (3)

92 (3)

Table 34. Dissolution rate of microcapsules containing 17% average weight of ethylcellulose (sample 9-D) in various dissolution media.

Dissolution medium

Percentage drug release (SD) n = 3

Zero minutes

5 minutes

15 minute

30 minute

45 minute

The second JP fluid has a pH of 6.8

0

34 (3)

83 (5)

97 (2)

97 (1)

1 mM HCL (pH 3.0)

0

36 (2)

93 (2)

97 (1)

97 (1)

DI water

0

35 (3)

74 (3)

88 (1)

96 (1)

The dissolution rates of a sample seed bag sample 33, containing a 9-d microcapsule sample (17% by weight of average ethylcellulose) are shown in Table 35 below.

Table 35. Dissolution rate of fexofenadine microcapsule/pellet mixtures containing microcapsules with 17% average weight of ethylcellulose (sample 33) in various dissolution media

Dissolution medium

Percentage drug release (SD) n = 3

Zero minutes

5 minutes

15 minute

30 minute

45 minute

The second JP fluid has a pH of 6.8

0

37 (1)

84 (3)

96 (2)

95 (1)

1 mM HCL (pH 3.0)

0

52 (4)

93 (3)

96 (3)

96 (2)

DI water

0

41 (1)

80 (1)

89 (1)

90 (0)

The dissolution rates of the formulated prototypes are similar to the dissolution profile of the corresponding microcapsules. The inactive ingredient(s) used did not affect the dissolution profile of the microcapsules.

2-3-3 Second set of examples For mixing the fexofenadine microcapsules that were formulated with the SC and SGX granulation products, a second set of fexofenadine products was prepared (Table 36). The compositions were prepared based on the following criteria:

(1) Prototypes were formulated using microcapsules with 13% or 15% encapsulation;

(2) β-cyclodextrin was not used;

(3) A single amount of flavoring agent, banana or strawberry, was used for all prototypes;

(4) The flavoring agent was introduced into the preparation which was mixed with the SG granulation product and with a small amount of silicon dioxide.

Table 36. Composition of the second group of fexofenadine prototypes

Sample 40

Sample 41

Sample 42

Sample 43

fexofenadine microcapsule 13%

36.0

36.0

fexofenadine microcapsule 15%

37.0

37.0

Granulating product SG + banana flavor + silicon dioxide

150.0

150.0

Granulating product SG + strawberry flavor + silicon dioxide

150.0

150.0

SGX granulation output

400.0

400.0

400.0

400.0

Total (mg)

586.0

587.0

586.0

587.0

Fexofenadine was released using a rapid mechanism (i.e., ≥80% release in 15 minutes) (Table 37).

Table 37. “In vitro” solubility values for fexofenadine using a second JP fluid, pH 6.8, from a second set of prototypes.

Percentage drug release (SD) n = 3

Zero minutes

5 minutes

15 minute

30 minute

45 minute

Sample 40 (13%)

0

65 (2)

95 (4)

96 (3)

96 (3)

Sample 41 (15%)

0

60 (2)

97 (3)

97 (3)

3)

2-3-3 The third set of examples of mixing fexofenadine microcapsules formulated with SGX granulation products. Additional prototypes were prepared as follows. The fexofenadine microcapsules were mixed with SGX granules, and the amount of xanthan gum was reduced from 1.5 to 1.1% w/w in the SGX granulation product so that the xanthan gum concentration remained equal to 1.0% w/w.

Table 38. Composition of the third group of fexofenadine prototypes

T1 drug test

T2 drug test

mg

٪

mg

٪

Fexofenadine microcapsules

36.00

6.15

37.0

6.30

Granulation product of sucrose/xanthan gum (1.1% w/w)

549.10

93.70

549.10

93.55

Silicon dioxide

0.60

0.10

0.60

0.10

Strawberry flavour

0.30

0.05

0.30

0.05

Total

586.00

100.00

587.00

100.00

2-4 Preparation of examples of fexofenadine granules

2-4-1 The first group of granulation of fexofenadine microcapsules with sucrose and xanthan gum

One part of fexofenadine microcapsules (15% by weight of ethylcellulose) is granulated with 6 parts of sucrose powder in a fluid bed equipped with a sprayer (Glatt GPCG3). The binder solution consisting of an aqueous solution of sucrose (15% w/w) and xanthan gum (0.5% w/w) was sprayed at room temperature. At the end of the granulation process, the granules were dried, then the dried granules were removed from the fluid bed and sieved.

The granules are characterized by particle size distribution (oscillatory sieving test), and release profile of fexofenadine (dissolution test in USP II apparatus, using 900 ml buffer solution pH 6.8, Japanese Pharmacopoeia II, at 37°C, stirrer speed of 50 rpm). microflora, uniformity of appearance and content of the active ingredient (optical microscopic test).

Content uniformity tests show that the fexofenadine microcapsules are homogeneously distributed into granules: the average measured content (n = 15) and the relevant %RSD are 111 mg/g (theoretically adjusted according to the microcapsule test: 114 mg/g) and 3 .2%, respectively.

Optical microscopic measurement shows that the granulation process results in the embedding of microcapsules in sucrose granules or the adhesion of microcapsules on sucrose granules.

Table 39. Size distribution of the obtained granules and the corresponding microcapsules

Sieve opening

Quantity of retained granules

The amount of initial microcapsules retained

Micrometer

% w/w

% w/w

600

0.0 (0.0)

nothing

500

2.7 (0.2)

nothing

355

21.5(1.1)

0.0(0.0)

250

38.9(1.0)

0.1(0.1)

212

16.3(0.3)

0.2(0.0)

180

8.7(0.8)

0.3(0.1)

125

7.8(0.6)

1.1(0.3)

90

2.5(0.2)

26.1(1.5)

Bottom

1.7(0.3)

72.3(1.7)

Table 40. Amount of fexofenadine released from the granules and from the corresponding microcapsules in buffer solution pH 6.8 (Japanese Pharmacopoeia Fluid II).

Release microcapsules

Editing sample granules 44

Time (minutes)

Theoretical percentage

(n=6)

Theoretical percentage

(n=6)

5

69 (3)

64 (1)

15

97 (1)

93 (4)

30

99 (1)

94 (2)

45

98 (1)

93 (3)

2-4-2 The second set of examples of granulating fexofenadine microcapsules with sucrose and xanthan gum. One part of fexofenadine microcapsules (15% by weight of ethylcellulose) is granulated with 14 parts of sucrose powder in a fluid layer equipped with a sprayer (Glatt GPCG3). The binder solution consisting of an aqueous solution of sucrose (15% w/w) and xanthan gum (0.5% w/w) was sprayed at room temperature. At the end of the granulation process, the granules were dried, then the dried granules were removed from the fluid bed and sieved.

Characterization of the collected granules by particle size distribution (oscillatory sieving test) and release profile of fexofenadine (dissolution test in USP II apparatus, using 900 ml buffer solution pH 6.8, Japanese Pharmacopoeia II, at a temperature of 37°C, and a stirrer speed of 50 rpm), uniformity of appearance and active ingredient content (optical microscopic test).

Content uniformity tests show that the granules are homogeneously distributed:

The average content and %RSD are respectively 53.5 mg/g (theoretical value adjusted according to microcapsule test: 54.5 mg/g) and 2.8% respectively.

The appearance of the granules (light microscopic scale) is close to the granules prepared in the first group using the same batch of microcapsules.

The granulation process was also confirmed by size distribution data (vibration sieving test):

Agglomeration of sucrose and microcapsules resulted in a significant increase in particle size (Table 41). Moreover, the granule size distribution is similar to that of the granules obtained in the first group (microcapsules/sucrose weight ratio 6:1).

Table 41. Size distribution of granules obtained in the first group and the corresponding microcapsules

Sieve opening

Quantity of retained granules

The amount of initial microcapsules retained

Micrometer

% w/w

% w/w

600

0.0 (0.0)

nothing

500

1.2 (0.2)

nothing

355

13.7 (0.8)

0.0 (0.0)

250

41.1 (1.0)

0.1 (0.1)

212

20.3 (0.1)

0.2 (0.0)

180

10.9 (0.8)

0.3 (0.1)

125

9.2 (0.5)

1.1 (0.3)

90

2.1 (0.2)

26.1 (1.5)

Bottom

1.5 (0.3)

72.3 (1.7)

Table 42. Amount of fexofenadine released from the granules and from the corresponding microcapsules in buffer solution pH 6.8 (Japanese Pharmacopoeia Fluid II).

Release microcapsules

Editing sample granules 44

Time (minutes)

Theoretical percentage

(n=6)

Theoretical percentage

(n=6)

5

69

(6)

64

(1)

15

97

(4)

93

(4)

30

99

(4)

94

(2)

45

99

(4)

93

(3)

2-4-3 The third set of examples of granulating fexofenadine microcapsules with sucrose and xanthan gum. A homogeneous final mixture was obtained by granulating the fexofenadine microcapsules with a portion of the excipients, then mixing them with the remaining inactive ingredients in granulated form. Mixtures of the same particle size are mixed at a 1:1 w/w ratio. The co-granulation process is carried out in a fluid bed equipped with a horizontal sprinkler in the laboratory scale (GPCG3 18.5cm). The microcapsules are mixed 6:1 w/w with sucrose and granulated using a binder solution of aqueous sucrose solution (5% w/w) containing 0.5% w/w xanthan gum.

>600 µm

500 Micrometer

355 Micrometer

250 Micrometer

212 Micrometer

180 Micrometer

125 Micrometer

90 Micrometer

<90 µm

Sample 45

0.2

1.3

4.7

19.5

19.4

15.1

22.9

9.0

7.9

Sample 46

0.3

4.4

24.7

38.9

14.9

7.5

6.3

1.8

1.1

U9A333

0.0

0.6

6.3

24.6

20.4

14.2

20.5

7.7

5.8

Sample 44

0.0

2.7

21.5

38.9

16.3

8.7

7.8

2.5

1.7

Sample 47

0.0

1.8

10.1

26.7

16.2

12.2

18.2

6.6

8.2

Sample 48

3.9

6.9

26.3

36.8

13.3

6.3

5.3

0.9

0.2

Sample 49

4.1

7.3

31.0

38.8

11.1

4.0

2.5

0.4

0.5

Sample 50

3.9

5.5

23.9

38.8

15.3

7.1

4.7

0.7

0.1

A single batch of granulation product, sample 45, is prepared by mixing microcapsules at a ratio of 6:1 w/w with sucrose using a binder solution of aqueous sucrose solution (5% w/w) in the absence of xanthan gum. The addition of xanthan gum and simultaneous increase of the amount of sucrose results in co-granulation of the microcapsules with sucrose. Table 43 shows the PSD of the resulting granulation products and drug test f (PSD):

Table 43. PSD of co-granulation process performed at laboratory scale

The theoretical test value is always 100 mg/g for all granulation products prepared. Observation of microcapsules shows that the soft fraction (<125 microns) is richer in microcapsules when compared to the larger fractions.

The melting values of the granulation products that were prepared “in the laboratory” are shown below.

Table 44. Dissolution values and drug tests for granulation products at laboratory scale

Paid

The second JP fluid has a pH of 6.8

CUT(n=15)

5 minutes

15 minute

30 minute

45 minute

Sample 46

503

892

951

941

113.5 (RSD 2.6)

Sample 44

641

934

942

933

111.0 (RSD 3.2)

Sample 48

442

792

932

952

108.7 (RSD 2.4)

Sample 49

572

961

991

992

112.5 (RSD 0.7)

In order to control the fraction of small particles, the parameters of the granulation process and the amount of binder solution can be adjusted.

The diagram shown in Figure 28 relates three process variables: the amount of binder solution sprayed onto the powder, the inlet air humidity, and the atomization air pressure. Granules with a lower percentage of fine fraction (values are indicated on the octagonal corners in the figure) are generated using the lowest atomization pressure, greater volume of binder solution and appropriate inlet air humidity. The obtained co-granulation product has a fine fraction <3% and a drug content with an RSD (relative standard deviation) of <3.0%.

2-4-4 The fourth set of examples of granulating fexofenadine microcapsules with sucrose and xanthan gum. Industrial scale.

Wet microcapsules are co-pelletized with fine sucrose granules using the same binder solution used during laboratory scale studies. Specifically, 14.70 kg of wet microcapsules were granulated with 102.90 kg of fine sucrose powder (7:1 ratio), using 29.40 kg as binder solution. The obtained granulation product was sieved through a 840 μm stainless steel sieve. The sifted product was placed in a double PE bag in plastic drums.

Table 45. Theoretical composition of fexofenadine co-granulation products - sample 52.

the components

% w/w

The fexofenadine

9.93

ethylcellulose

1.75

sodium docusate

0.07

silicon dioxide

0.27

sucrose

87.86

xanthan gum

0.12

The obtained granulation products are characterized in terms of PSD, test drug as f(PSD), water content (0.13%) and “in vitro” solubility values in a second JP fluid pH 6.8. The data is shown in the following tables.

Table 46. PSD of co-granulation products prepared on an industrial scale

>600 µm

500 Micrometer

355 Micrometer

250 Micrometer

212 Micrometer

180 Micrometer

125 Micrometer

90 Micrometer

<90 µm

Sample 51

21.9

17.5

32.9

21.7

3.9

1.3

0.9

0.0

0.0

Sample 52

4.6

6.5

19.4

29.5

15.5

9.5

10.9

2.7

1.4

Table 47. Solubility values in buffer solution pH 6.8, second JP fluid “in the laboratory” and test (n = 3).

a sample

the heart

The second JP fluid has a pH of 6.8

Test(mg/g)

RSD%

5 minutes

15 minute

30 minute

45 minute

Sample 52

Sample 18

553

884

914

914

98.6

3.9

The amount of fine particles is low. The RSD value ranges between 1.8% and 6.0%.

2-4-5 Preparation of sucrose and xanthan granulation products

Sucrose granules are prepared that have a PSD similar to that obtained with the co-granulation product. Scale-up is performed directly on the industrial fluid bed equipped with a Glatt FB500, 500 L overhead sprayer. The process is performed in one step: the xanthan gum is directly granulated with sucrose by spraying the same binder solution used for the co-granulation process, except that the ethanol is eliminated.

In particular, 147.0 kg of fine sucrose powder is granulated with 3.0 kg of xanthan gum with 20.0 kg of binder solution. At the end of the granulation process, the product is sieved through a stainless steel sieve with a size of 840 micrometers, and 149.1 kg of granulation product is obtained (process yield 97.4%).

Table 48. Theoretical composition of the binder solution and the granulation product of sucrose/xanthan gum sample 53.

the components

% w/w

kg

Sample composition 53%

Binding solution

sucrose

15.0

3.0

2.0

xanthan gum

0.5

0.1

0.1

Deionized water

84.5

16.9

-

powder

Fine sucrose powder

88.0

147.0

96.0

xanthan gum

2.0

3.0

1.9

The PSD and water content (0.48%) of the resulting granulation products were characterized.

Table 49. Particle size analysis of sample 53 and sample 54.

sieve (micrometer)

Sample 53(%)

Sample 54 (%)

>600

8.6

5.7

500

9.4

9.9

355

23.5

25.3

250

30.2

31.8

212

11.2

11.2

180

7.1

5.9

125

6.7

6.3

90

1.7

1.7

<90

1.3

2.2

The two granulation products were prepared applying the same process variables and resulted in formulations that had the same PSD compared to the co-granulation product (this is an important requirement in order to ensure that the next mixing step can be performed successfully).

2-5 Mix fexofenadine granules and sucrose granules

The previous two batches of co-granulation products and sucrose granulation products were blended with two batches of granules of a sugar-based active free drug with a very similar PSD, in a 1:1 w/w ratio with batch sizes of approximately 200 kg. The combination of sample 51 and the active ingredient-free drug sample 55 is referred to as sample 56 after mixing.

Table 50. PSD of the number of batches of the mixture, sample 56, sample 51 (co-granulation products), and sample 55 (sucrose granulation products):

>600 µm

500 Micrometer

355 Micrometer

250 Micrometer

212 Micrometer

180 Micrometer

125 Micrometer

90 Micrometer

<90 µm

Sample 51

21.9

17.5

32.9

21.7

3.9

1.3

0.9

0.0

0.0

Sample 55

18.7

16.2

30.9

23.1

5.3

2.1

1.9

0.7

1.4

Table 51. PSD of the number of batches of the mixture: sample 57, sample 52 (co-granulation products), and sample 53 (sucrose granulation products):

>600 µm

500 Micrometer

355 Micrometer

250 Micrometer

212 Micrometer

180 Micrometer

125 Micrometer

90 Micrometer

<90 µm

Sample 52

4.6

6.5

19.4

29.5

15.5

9.5

10.9

2.7

1.4

Sample 53

8.6

9.4

23.5

30.2

11.2

7.1

6.7

1.7

1.3

The following tables describe the composition of payments.

Table 51. Theoretical structure of payments.

the components

Sample 56, Sample 57 (%)

The fexofenadine

5.00

ethylcellulose

0.88

sodium docusate

0.04

Silicon dioxide

0.22

sucrose

92.75

xanthan gum

1.06

Strawberry flavour

0.05

Table 53. Drug Test and RSD%:

Paid

Drug test (mg/g),

n=3

Theoretical test (mg/g)

%RSD

Sample 56

48.1

50.0

5.6

Sample 57

49.0

50.0

3.9

The mixing uniformity (n = 10) for sample mixture 57: first test is 50.5 mg/g (RSD 5.1%); Second test: 50.7mg/g (RSD5.5%). The experiments performed indicate that the test average is close to the theoretical value (50 mg/g). The dissolution performance of the bulk mixture of fexofenadine (sample 57) in a buffer solution of a second JP fluid at pH 6.8 (compared to the product of the specific granulation (sample 52) (n = 6)) at pH 3.0 is shown below.

Table 54. Dissolution profiles of the mass mixture of fexofenadine (sample 57) and its co-granulation product (sample 52) (n = 6) in a buffer solution of a second JP fluid, pH 6.8.

Time (minutes)

5

15

30

45

60

Sample 52

553

825

884

914

914

925

Sample 57

622

867

905

924

914

914

The mixing process shows a slight increase in the dissolution rate during the first five minutes, this effect can be linked to the mechanical stress present during mixing

Table 55. Solubility profiles of the mass mixture of fexofenadine (sample 57) at pH 3.0

Time (minutes)

5

10

15

30

45

60

% of fexofenadine released

6310

8410

929

958

948

948

Confirm sample dissolution data 57 rapid release.

2-6 Filling the seed bag

A strength of 15 mg was obtained corresponding to 300 mg of the mixture. The packing tool produces two zipper bags in series (7.0mm-5.8mm). The maximum productivity is 170 bags of seeds/minute (speed 85 rpm). The material used in preparing the seed bags is 3LAMINET/M AL12960 (PET 12 micrometres, aluminum 9 micrometres, static PE 60 micrometres).

A feeding screw is placed between the bag and the feeding hopper aligned with a sensor to detect the amount of powder in order to keep the amount of mixture in the hopper consistent (when the mixture volume is reduced, the screw feeds the hopper).

The hopper has two sections, left and right filling system, and each side is equipped with a single dosing screw. Inside there are two stirring systems (left and right) that keep the mixture gently stirred during the process. The seed bag filling experiments are performed starting from the mixture prepared using a co-granulation product with different levels of fine particles and PSD. In some cases the theoretical test value of the mixture is lower and therefore the target strength for each drug content can be variable.

A seed bag for sample 58 is prepared using the mass mixture of sample 57 (50.0 mg/g RSD 5.6%). The mass mixture of sample 57 is shown in Table 51. The machine variables that were set are shown in the following table.

Table 56. Packing process machine variables

Variables

Value

Machine speed

85 rpm

Flow stopper

1.6 mm

Weight control on the production line at the outlet

54.5 g 0.7 g

Table 57. Limits of sample acceptance 58.

the exams

Acceptance limits

the weight

285 315 mg

Mass content

T1 = 3.0% (9 mg)

T2 = 5.0% (15 mg)

Table 58. Sample test results 58.

Shipping box

2

4

6

a sample

Weight(mg)

Test (mg/bag)

Weight(mg)

Test (mg/bag)

Weight(mg)

Test (mg/bag)

302.1

15.2

295.3

14.4

298.2

14.4

2

310.8

15.5

297.3

14.4

296.2

14.2

3

310.7

15.4

309.9

15.1

300.1

14.0

4

314.8

16.1

307.3

15.1

300.0

14.1

5

316.1

15.6

302.2

14.9

304.1

14.6

6

298.5

15.3

322.7

15.6

291.6

14.8

7

313.5

16.1

306.4

14.7

290.2

14.0

8

310.3

15.8

294.2

14.4

298.8

14.3

9

305.8

15.9

307.2

15.2

297.0

14.3

10

304.9

15.7

307.2

14.6

297.4

14.4

Average

308.8

15.7

305.0

14.8

297.4

14.3

Sd

5.7

0.3

8.4

0.4

4.1

0.3

RSD

1.8

1.9

2.8

2.7

1.4

2.1

%extraction

104.7

98.7

95.3

Mass change

Regularity of content

Mass change

Regularity of content

Mass change

Regularity of content

AV

7.8

8.0

6.5

6.5

6.3

7.2

The results indicate that a 300 mg seed bag with a mass variation of 6.3 to 7.8 and a content uniformity of 6.5 to 8.0 was obtained using the co-granulation product of the fexofenadine microcapsule of the invention.

2-6-2 Fill the seed bag with a sample mixture of >125 micrometers

The mass mixture of sample 57 >125 microns is prepared from sample 57 by removing the fine fraction (<125 microns); Which is made using palm trees. The PSD data for the mixture is shown in Table 59.

Table 59

Palm trees

Sample 57 >125µm

>600

10.0

355

37.0

212

39.2

125

13.1

>125

0.5

The seed bag filling experiments were conducted on a 15 mg seed bag using the mass mixture. The batch number for the sample 79 seed bags is obtained. The following table summarizes the results:

Table 60. Sample test results 79.

Shipping box

2

4

8

a sample

Weight(mg)

Test (mg/bag)

Weight(mg)

Test (mg/bag)

Weight(mg)

Test (mg/bag)

318.6

14.1

316.1

13.5

303.7

13.6

2

319.6

14.2

294.5

13.8

307.4

13.9

3

308.4

13.9

310.6

13.7

306.3

13.5

4

319.8

14.2

305.2

13.3

305.3

13.9

5

319.0

14.0

302.7

14.2

306.8

14.0

6

313.6

14.0

301.3

13.2

306.2

13.4

7

317.3

14.0

312.8

13.5

304.5

13.5

8

319.1

14.3

298.5

13.1

314.8

13.9

9

309.9

13.7

310.4

13.7

313.1

13.6

10

325.6

14.5

303.5

12.9

302.7

13.6

Average

317.1

14.1

305.6

13.5

307.1

13.7

Sd

5.1

0.2

6.8

0.4

3.9

0.2

RSD

1.6

1.4

2.2

3.0

1.3

1.5

%extraction

102.2

97.8

99.3

Mass change

Regularity of content

Mass change

Regularity of content

Mass change

Regularity of content

AV

4.6

4.5

5.9

7.4

3.0

3.7

Good results are obtained for the filling weight, however the starling bag test is practically equal to the theoretical value (13.8 mg/g); The phenomenon of separation did not appear.

Experiments were performed on a 15 mg sachet using a mass mixture of sample 56. The PSD of the mass mixture is shown in Table 61.

Shipping box

2

3

4

a sample

Weight(mg)

Test (mg/bag)

Weight(mg)

Test (mg/bag)

Weight(mg)

Test (mg/bag)

Weight(mg)

a test

(mg/bag of seed)

315.1

15.9

315.0

16.0

313.2

16.4

303.8

16.5

2

310.6

16.7

324.8

16.0

314.9

16.7

319.2

15.7

3

318.8

16.9

316.0

16.5

316.8

16.5

303.9

16.3

4

315.1

16.6

319.2

16.1

309.1

16.7

305.7

16.8

5

313.3

16.5

323.1

17.0

309.6

16.2

302.3

16.7

6

313.5

16.2

314.0

14.5

316.0

15.2

300.4

15.4

7

312.8

15.4

312.8

15.2

317.7

15.5

339.1

15.8

8

315.7

15.6

314.2

15.3

314.1

15.7

298.9

14.9

9

313.1

16.3

317.5

14.7

315.9

14.6

300.8

15.4

10

312.5

15.8

316.4

15.0

314.3

14.7

298.7

14.9

Average

314.1

16.2

317.3

15.6

314.2

15.8

307.3

15.8

Sd

2.1

0.5

3.8

0.8

2.7

0.8

12.0

0.7

RSD

0.7

2.9

1.2

4.9

0.9

4.8

3.9

4.2

%extraction

107.9

104.2

105.5

105.6

The test is dependent on the packing weight, and is always higher than the theoretical value of 300 mg; There is a complete absence of separation, the test remains highly consistent throughout the production process and is especially subject to change.

2-6-4 Filling the seed bag using industrial scale equipment

Additional experiments were performed using industrial-scale equipment; The batch size involved is on the order of hundreds of kilograms for the final mass mixture and in the order of hundreds and thousands for dosage units.

Fexofenadine co-granulation products are prepared starting from wet microcapsules. The particle size distribution of wet microcapsules is shown in Table 62.

Table 62. Particle size distributions of wet microcapsules (sieving method)

>355 µm

Between 355 and 125 micrometers

<125 µm

1.0

4.0

95.0

1.0

6.0

93.0

0.0

2.0

98.0

0.0

1.0

99.0

0.0

2.0

98.0

1.0

2.0

97.0

The granulation products are prepared and mixed with the components that were granulated. The three batches obtained have the same composition as the batches shown in Table 51. Experiments were conducted on these three batches.

The following table shows the data regarding the particle size distribution, for the mixtures and experiments, and the corresponding standard deviation of the seed bags obtained for the three batches:

Table 63. Particle size distribution of mixtures

Sample number

Sample 59

Sample 60

Sample 61

Sieve opening

% preserved by each sieving process

> 600 µm

8.2 1.0

9.6 0.7

13.2 2.1

> 355 µm

49.4 4.9

46.8 4.3

58.0 0.5

> 212 µm

36.2 2.5

37.1 2.6

25.4 0.4

> 125 µm

5.2 1.4

5.7 2.3

2.1 0.8

> 125 µm

0.7

0.7 0.4

1.2 0.7

Each batch of the mixture was used to prepare two batches of sachets, one for each expected dosage strength: 15 and 30 mg, where 30 mg corresponds to 600 mg of filling weight and 15 to 300 mg.

In more detail, each batch of mixture leads to an increase in batches of seed bags:

- Sample mixture: 59 sachets: 62 (300 mg) and 63 (600 mg).

- Sample mixture: 60 sachets: 64 (300 mg) and 65 (600 mg).

- Sample mixture: 61 sachets: 66 (300 mg) and 67 (600 mg).

The following table shows the experimental test values for each batch of seed bags produced:

Table 64. Testing for starling bags

Batch number

Practical test, mg/bag

practical test %

SD on the practical test

RSD on practical test

A62

14.9

99

0.4

2.7

A63

14.8

99

0.3

2.0

A64

15.2

101

0.3

2.0

A65

30.6

102

0.5

1.6

A66

30.3

101

0.7

2.3

A67

30.9

103

0.6

1.9

Furthermore, sachets of Zarur containing 600 mg of dry syrup were also analyzed for dissolution rate “in the laboratory”, a dissolution test was performed at pH = 3.0 using n = 12 samples. The following table shows data expressed as the percentage released after 15 minutes, the standard deviation and the relative standard deviation:

Table 65. “In vitro” dissolution data for 600 mg batches

Percentage fired

Standard deviation

Relative standard deviation

63

92

3.3

65

93

5

5.4

67

85

3

3.5

It is established from the above that it was possible to successfully prepare additional packing weights (600 and 300 mg per unit) and additional dosage strengths (15 mg and 30 mg of fexofenadine HCl per unit) for seed bags containing dry syrup.

It should be recognized that, although specific embodiments of the invention are described herein for illustrative purposes, certain modifications may be made without departing from the substance and scope of the invention.