Sildenafil pharmaceutical preparations

Abstract

A solid pharmaceutical formulation comprising a mixture of (1) freeze-dried granules containing sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient and (2) a non-lyophilized composition, wherein the formulation comprises 35% to 50% by weight of the freeze-dried granules (1), dissolves in the oral cavity, and the non-lyophilized composition (2) is a solid blend composition containing a glidant; packaging containing the formulation; and a process for producing the formulation.

Description

[Technical Field]

[0001] The present invention relates to solid pharmaceutical formulations of sildenafil or a pharmaceutically acceptable salt thereof, processes for their preparation, and solid blend compositions for use in preparing the pharmaceutical formulations. [Background technology]

[0002] Pharmaceutical dosage forms that dissolve rapidly when placed in a patient's mouth, thereby delivering a desired dose of a pharmaceutically active substance, are particularly useful if the dosage form can be taken without water. Such dosage forms are generally preferred for people who have difficulty swallowing and / or taking tablets or capsules.

[0003] Fast-dissolving dosage forms are generally prepared using multi-step processes, some of which involve a freeze-drying step during which solvent is removed from a solution and / or suspension consisting of a pharmaceutically active substance, a carrier material, and a solvent.

[0004] Although pharmaceutical formulations produced by freeze-drying have various advantages, they also have various problems such as free flow, hygroscopicity, bitterness, dosage uniformity, content uniformity, and pharmacokinetic problems, etc. The present invention aims to overcome these problems. Summary of the Invention

[0005] The present invention provides a novel blend composition of sorbitol and liquid paraffin for use in improving the formulation properties of pharmaceutical formulations in several parameters, namely, flow properties, moisture resistance, antistatic properties, and compressibility (Carr index). The blend composition also contains tartaric acid and / or citric acid to improve the dissolution properties, especially of pharmaceutical formulations containing sildenafil.

[0006] Accordingly, the present invention provides a solid pharmaceutical formulation comprising a mixture of (1) lyophilized granules comprising sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient, and optionally a base, and (2) a non-lyophilized composition, which is a solid blend composition comprising a glidant.

[0007] The present invention further provides a solid blend composition comprising or consisting of sorbitol, liquid paraffin, and optionally tartaric acid and / or citric acid, for use in the manufacture of the pharmaceutical formulation of the present invention.

[0008] The present invention also provides (a) forming lyophilized granules (1) by sublimating a solvent from a preparation comprising sildenafil or a pharmaceutically acceptable salt thereof and a solvent; (b) forming a solid blend composition (2) comprising or consisting of sorbitol, liquid paraffin, and an organic acid selected from one or both of tartaric acid and citric acid; and (c) mixing the solid blend composition (2) obtained in step (b) with the freeze-dried granules (1) obtained in step (a); The present invention provides a process for producing the solid pharmaceutical formulation of the present invention, comprising: [Brief explanation of the drawings]

[0009] [Figure 1] The dissolution rates in water of the formulations of Examples 1 to 4 and commercially available Viagra (registered trademark) 100 mg tablets are compared. [Figure 2] The dissolution rates in water of the formulations of Comparative Examples A to D and commercially available Viagra® 100 mg tablets are compared. [Figure 3] 1 is a photograph of a stick pack of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0010] The pharmaceutical formulation of the present invention dissolves in the oral cavity and comprises 35% to 50% by weight of freeze-dried granules (1) together with a non-lyophilized composition (2), which is a solid blend composition containing a glidant.

[0011] In one embodiment, the formulation, upon oral administration to a human subject, provides at least one of the following pharmacokinetic parameters: AUC (0-10 min) of at least 3.5 ng·h / mL; and AUC (0-30 min) of at least 150 ng·h / mL. The AUC values ​​are determined as further described in the Experimental Section.

[0012] The glidant in the solid blend composition (2) is preferably represented by a combination of sorbitol and liquid paraffin.

[0013] In one embodiment, the pharmaceutical formulation of the present invention comprises 0.01% to 30% by weight of an active ingredient, 35% to 50% by weight of lyophilized granules (1), 50% to 65% by weight of a solid blend composition (2), and 0% to 15% by weight of one or more pharmaceutically acceptable excipients as further components of the formulation, wherein the solid blend composition (2) comprises 85% to 93% by weight of sorbitol, 5% to 14.9% by weight of an organic acid selected from one or both of tartaric acid and citric acid, and 0.1% to 5% by weight of liquid paraffin. Preferably, the solid blend composition (2) comprises 90.5% to 92.0% by weight of sorbitol, 5.0% to 9.0% by weight of an organic acid selected from one or both of tartaric acid and citric acid, and 0.5% to 3.5% by weight of liquid paraffin.

[0014] The formulation preferably contains 10% to 20% by weight of the active ingredient, 37.5% to 42.5% by weight of the lyophilized granules (1), 57.5% to 62.5% by weight of the solid blend composition (2), and 0.0% to 5.0% by weight of one or more pharmaceutically acceptable excipients as further components of the formulation.

[0015] In one embodiment, the formulation comprises 37.5% to 42.5% by weight of freeze-dried granules (1) and 57.5% to 62.5% by weight of a solid blend composition (2), wherein the solid blend composition (2) comprises 90.5% to 92.0% by weight of sorbitol, 5.0% to 9.0% by weight of an organic acid selected from one or both of tartaric acid and citric acid, and 0.5% to 3.5% by weight of liquid paraffin.

[0016] In one embodiment, the active ingredient of the formulation of the present invention is sildenafil citrate.

[0017] In one embodiment, the organic acid is tartaric acid.

[0018] In one embodiment, the solid pharmaceutical formulation is a free-flowing formulation.

[0019] The lyophilized granules (1) contain sildenafil or a pharmaceutically acceptable salt thereof, and may optionally further contain pharmaceutically acceptable excipients, particularly those conventionally used in processes for producing lyophilized granules. The pharmaceutically acceptable excipient can be selected from sugars, sugar alcohols, monosaccharides, disaccharides, trisaccharides, polysaccharides, proteins, amino acids, gums, etc., including, but not limited to, mannitol, trehalose, raffinose, inositol, pullulan, sucrose, lactose, dextrose, erythritol, xylitol, lactitol, maltitol, isomalt, alanine, arginine, threonine, glycine, cysteine, serine, histidine, valine, proline, lysine, asparagine, glutamine, ribose, glucose, galactose, fructose, maltose, maltotriose, guar gum, xanthan gum, tragacanth gum, veegum, etc. Generally, the lyophilized granules (1) are paraffin-free. In one embodiment of the present invention, the freeze-dried granules (1) further comprise a base such as one or more selected from sodium hydroxide, potassium hydroxide, magnesium hydroxide, aluminum hydroxide and calcium hydroxide, preferably sodium hydroxide.

[0020] In one embodiment of the present invention, the lyophilized granules (1) contain 35% to 46% by weight of sildenafil or a pharmaceutically acceptable salt thereof (preferably sildenafil citrate), 39% to 65% by weight of a sugar alcohol (preferably mannitol), and 0% to 15% by weight of a base (preferably sodium hydroxide). More preferably, the lyophilized granules (1) contain 35% to 44% by weight of sildenafil or a pharmaceutically acceptable salt thereof (preferably sildenafil citrate), 46% to 60% by weight of a sugar alcohol (preferably mannitol), and 5% to 10% by weight of a base (preferably sodium hydroxide). The proportion of the base is preferably selected so that the weight ratio of the organic acid in the solid blend composition (2) to the base in the lyophilized granules (1) is at least 1.6:1, more preferably at least 2:1. There is no particular upper limit to the weight ratio of the organic acid to the base. This ratio may be up to 10:1, or up to 5:1.

[0021] The solid blend composition (2) preferably contains 85% to 93% by weight of sorbitol, 5% to 14.9% by weight of an organic acid selected from one or both of tartaric acid and citric acid, and 0.1% to 5% by weight of liquid paraffin. The solid blend composition (2) more preferably contains 90.5% to 92.0% by weight of sorbitol, 5.0% to 9.0% by weight of an organic acid selected from one or both of tartaric acid and citric acid, and 0.5% to 3.5% by weight of liquid paraffin. Generally, the solid blend composition (2) does not contain any active ingredient.

[0022] In addition to the components (1) and (2) described above, the formulation may also contain other excipients (auxiliaries, adjuvants), such as, but not limited to, fillers, thickeners (including, but not limited to, guar gum and xanthan gum), binders, diluents, lubricants, pH adjusters, protectants, viscosity enhancers, wicking agents, non-effervescent disintegrants, effervescent disintegrants, surfactants, antioxidants, humectants, colorants, flavoring agents, taste-masking agents, sweeteners, and preservatives.

[0023] In one embodiment of the present invention, the formulation is obtained by a process of the present invention comprising the steps of forming a solid blend composition (2) by blending sorbitol, liquid paraffin, and an organic acid selected from one or both of tartaric acid and citric acid, and adding the solid blend composition (2) to an active ingredient in the form of lyophilized granules (1).

[0024] The present invention further provides a novel solid blend composition comprising or consisting of sorbitol, liquid paraffin, and an organic acid selected from one or both of tartaric acid and citric acid, for use in the preparation of a pharmaceutical formulation containing sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient. The solid blend composition preferably comprises 85% to 93% by weight of sorbitol, 0.1% to 5% by weight of liquid paraffin, and 5% to 14.9% by weight of an organic acid selected from tartaric acid and citric acid. More preferably, the solid blend composition comprises 90.5% to 92.0% by weight of sorbitol, 0.5% to 3.5% by weight of liquid paraffin, and 5.0% to 9.0% by weight of an organic acid selected from tartaric acid and citric acid. In one embodiment, the blend composition comprises the indicated components in the preferred and more preferred proportions shown.

[0025] The present invention also provides (a) forming lyophilized granules (1) by sublimating a solvent from a preparation comprising sildenafil or a pharmaceutically acceptable salt thereof and a solvent, and optionally a base; (b) forming a solid blend composition (2) comprising or consisting of sorbitol, liquid paraffin, and an organic acid selected from one or both of tartaric acid and citric acid; (c) mixing the solid blend composition (2) obtained in step (b) with the freeze-dried granules (1) obtained in step (a); The present invention provides a process for producing the solid pharmaceutical formulation of the present invention, comprising:

[0026] The blend composition of sorbitol and liquid paraffin (2) is mixed with the lyophilized granules (1) by methods known in the art such as geometric mixing or mixing in any kind of blender.

[0027] The process of the present invention makes it possible to obtain solid pharmaceutical formulations in the form of free-flowing granules, which are a preferred embodiment of the present invention.

[0028] The preferred proportions of the active ingredient, sorbitol, liquid paraffin, organic acid and solid blend composition, as well as the preferred types and proportions of optional additional pharmaceutically acceptable excipients, particularly bases, in the process of the present invention are the same as those in the pharmaceutical formulation of the present invention.

[0029] The solvent used in lyophilized preparations containing the active ingredient and, optionally, further pharmaceutically acceptable excipients such as sugar alcohols and bases is typically water.

[0030] The terms "active ingredient" and "pharmaceutically active ingredient" are used interchangeably herein.

[0031] The preferred route of administration for the dosage forms of the present invention is oral administration.

[0032] In one embodiment, the pharmaceutical formulation of the present invention may be administered to a patient in the form of granules.

[0033] In another embodiment, the pharmaceutical formulations of the present invention are contained in a package (also referred to as a unit dosage form) that dispenses a single dose of the formulation. Non-limiting examples of packages / unit dosage forms are sachets and stick packs.

[0034] In another embodiment, the pharmaceutical formulations of the present invention, for example in the form of granules, are packaged in a multi-dosage form, i.e., in a dosage form from which multiple doses of any size can be withdrawn. Non-limiting examples of multi-dosage forms are bottles and any other containers capable of holding granules.

[0035] A patient administered the free-flowing granular formulation of the present invention is assured of receiving the entire dose, i.e., no residue is left behind in the package / unit dosage form.

[0036] In one embodiment, oral administration is achieved by emptying a sachet, stick pack or (any other) unit pack containing the granules onto the tongue and swallowing the contents.

[0037] In another embodiment, oral administration is performed by dissolving the granules in a solvent (eg, a glass of water) and then drinking the solution.

[0038] The exact dosage and administration regimen of the dosage form will necessarily depend on the therapeutic effect to be achieved and may vary with the route of administration, as well as the age and condition of the individual subject to whom the formulation is to be administered. A patient may optionally be instructed to take two or any other number of unit dosage forms, e.g., stick packs, in a single dose, or may optionally be instructed to take only a portion, e.g., half or a quarter of a unit dosage form, in a single dose.

[0039] The formulations of the present invention are unique in that they have improved flow properties, moisture content, antistatic properties and compressibility, and exhibit improved pharmacokinetic properties upon administration. [Example]

[0040] The invention is further described in the following examples, which are not intended in any way to limit the scope of the invention as claimed.

[0041] [Table 1]

[0042] [Table 2]

[0043] [Table 3]

[0044] [Table 4]

[0045] [Table 5]

[0046] Manufacturing Procedure I. Freeze-dried granules 1. Sodium hydroxide was dissolved in 370 mL of purified water while stirring with an overhead stirrer. 2. Sildenafil citrate was dispersed evenly in the solution from step 1 with stirring. 3. The dispersion obtained in step 2 was homogenized using a homogenizer and an overhead stirrer. 4. Hydroxypropyl cellulose L was dissolved in water (166.5 g) and this solution was added to the dispersion from step 2 with stirring. 5. Mannitol was added to the dispersion. 6. The final weight of the solution / dispersion was brought to 1200g using purified water. 7. The solution / dispersion was kept mixed using a magnetic / overhead stirrer. 8. The solution / dispersion was filled into stainless steel trays and freeze-dried in a freeze dryer. 9. After complete freeze-drying, the freeze-dried cake was sieved through a #40 sieve to obtain freeze-dried granules.

[0047] II. Blend Composition 10. Sorbitol was passed through a #40 sieve and neotame with orange flavor was passed through a #60 sieve. The sieved sorbitol, neotame and orange flavor were mixed in a high speed mixer granulator. 11. Liquid paraffin was added dropwise to the mixture (80 g) of step 10 and mixed to obtain a uniformly distributed composition. 12. The composition of step 11 was sieved through a #40 sieve and mixed with the mixture of step 10 using a rapid mixer granulator. 13. The mixture from step 12 was passed through a 40# sieve and transferred to a double cone blender. 14. The organic acid was added to the blender in step 13 and the mixture was blended to obtain a blended composition.

[0048] III. Formulation 15. The lyophilized granules of step 9 were mixed with the blended composition of step 14 in a double cone blender to obtain a free-flowing sildenafil formulation. 16. The free flowing formulation was filled into stick packs and sealed.

[0049] A comparative pharmaceutical formulation was prepared essentially as described in Example 1, with the following modifications.

[0050] [Table 6]

[0051] [Table 7]

[0052] [Table 8]

[0053] [Table 9]

[0054] In vitro dissolution In vitro dissolution testing was performed according to USP Type I basket (100#) at 100 rpm in 900 mL of water as the dissolution medium maintained at 37°C ± 0.5°C. The release profiles of Examples 1-4 compared to Viagra® 100 mg tablets are shown in Figure 1. The release profiles of Comparative Examples A-D compared to Viagra® 100 mg tablets are shown in Figure 2. The formulations according to Examples 1-4 showed comparable or faster release at 5 minutes compared to Viagra® 100 mg tablets.

[0055] Bioavailability of stable oral compositions A two-way randomized crossover study was conducted to compare the bioavailability of a 100 mg dose of Example 1 to Viagra® (sildenafil citrate) 100 mg film-coated tablets in 48 healthy adult males under fasting conditions.

[0056] During each study period, a single dose of the sildenafil citrate composition was administered orally in the morning after a 10-hour overnight fast. Fasting conditions were maintained for up to 4 hours after administration. Dosing was as follows:

[0057] Example 1 containing 100 mg of sildenafil citrate was administered orally to volunteers without water.

[0058] An oral dose of 100 mg Viagra® tablet was administered with approximately 240 mL of water.

[0059] Sildenafil plasma concentrations were determined by serial blood sampling, and sildenafil pharmacokinetic (PK) parameters were determined by noncompartmental analysis. Parameters of interest were peak plasma concentration (Cmax), area under the plasma concentration curve (AUC), time to peak plasma concentration (Tmax), and lag time to observed sildenafil concentration (Tlag). AUC was determined by the linear trapezoidal method.

[0060] [Table 10]

[0061] Evaluation 1: Bulk density and tapped density results Bulk density and tapped density are important for understanding the flow properties of a formulation. The bulk density of a material is the ratio of mass to volume (including interparticle void volume) of an untapped powder sample. Tapped density is the increased bulk density obtained after mechanically tapping a container containing a powder sample. Tapped density is obtained by mechanically tapping a graduated cylinder containing the sample until a small further change in volume is observed. Since the interparticle interactions that affect the bulk properties of a powder are also the interactions that hinder the powder's flowability, a comparison of bulk density and tapped density can provide a relatively significant measure of these interactions in a given powder. Such a comparison is often used as an index of a powder's flow ability, for example, the compressibility index or Hausner ratio: Compressibility Index (Carr Index):

[0062]

number

[0063]

number

[0064] Procedure for measuring bulk density: United States Pharmacopeia (USP) No. <616> Use a 100 mL cylinder readable to 1 mL and an amount of powder that will give an untapped apparent volume of 50-100 mL according to Method I in Chapter 1.

[0065] Procedure for measuring tap density: United States Pharmacopeia (USP) No. <616> According to Method I of Chapter, the details are as follows: · Attach a 100 mL measuring cylinder (readable to 1 mL) weighing 130 ± 16 g to a holder weighing 240 ± 12 g. Perform 10, 500, and 1250 taps on the powder sample and measure the volume V corresponding to the nearest scale unit. 10 , V 500 , and V 1250 Measure. ·V 500 and V 1250 If the difference is less than 1 mL, V 1250 is the tap volume. ·V 500 and V 1250 If the difference is more than 1 mL, the measurement is repeated in increments such as 1250 taps until subsequent measurements differ by 1 mL or less.

[0066] [Table 11]

[0067] Rating 2: Angle of repose: The angle of repose is used to characterize the flow properties of solids. It is a characteristic related to interparticle friction or the resistance to motion between particles. The angle of repose is the constant three-dimensional angle (with respect to the horizontal base) assumed by a conical pile of material.

[0068] Procedure (USP General Chapter <1174> by): The angle of repose is formed on a fixed base with a retaining lip to hold the powder layer on the base. The base must not vibrate. A symmetrical cone of powder is carefully constructed by varying the height of the funnel. Care must be taken to prevent vibration when moving the funnel. The height of the funnel should be kept approximately 2-4 cm from the top of the cone to minimize the impact of the powder falling onto the top of the cone as the pile of powder forms. If a symmetrical powder cone cannot be successfully or reproducibly prepared, this method is not suitable. The angle of repose is determined by measuring the height of the powder cone and using the following formula: tan(a)=height / 0.5base It can be calculated by calculating the angle of repose (a) from

[0069] [Table 12]

[0070] Rating 3: Moisture content: The pharmaceutical formulations were placed in open Petri dishes and then placed in Climacel maintained at 25°C / 75% relative humidity to simulate exposure to high humidity. After 1, 2, and 6 hours in Climacel, each formulation was analyzed for moisture content. Moisture content was assessed using the USP General Chapter 921 moisture determination method.

[0071] [Table 13]

[0072] Rating 4: Anti-sticking properties The anti-stick properties of the formulations were measured by determining the residual content using the following procedure.

[0073] procedure: The pharmaceutical formulation was uniformly filled into 10 stick packs made from plastic laminate as shown in Figure 3. The fill weight of each stick pack was noted for further reference. The filled stick packs were sealed using a sealing machine. The sealed stick packs were held on a vibrating sifter for 30 minutes to confine the formulation to the corners of the stick pack. Each stick pack was opened by cutting from one sealed side. The formulation was removed from each stick pack and weighed on a calibrated balance to determine the amount of formulation recovered from each stick pack. The residual content was calculated using the following formula: (Fill weight of stick pack) - (Content recovered from stick pack) = Residual content

[0074] [Table 14]

Claims

1. A solid pharmaceutical formulation comprising a mixture of (1) freeze-dried granules containing sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient and (2) a non-lyophilized composition, wherein the formulation contains 35% to 50% by weight of the freeze-dried granules (1), dissolves in the oral cavity, and the non-lyophilized composition (2) is a solid blend composition that includes a glidant.

2. 10. The solid pharmaceutical formulation of claim 1, which, upon oral administration to a human subject, provides at least one of the following pharmacokinetic parameters: AUC (0-10 min) of at least 3.5 ng h / mL; and AUC (0-30 min) of at least 150 ng h / mL.

3. 2. The solid pharmaceutical formulation of claim 1, wherein the glidant is a combination of sorbitol and liquid paraffin.

4. 4. The solid pharmaceutical formulation of claim 3, The formulation comprises 50% to 65% by weight of the solid blend composition (2), and 0% to 15% by weight of one or more pharmaceutically acceptable excipients as further components of the formulation; the solid blend composition (2) comprises 85% to 93% by weight of sorbitol, 5% to 14.9% by weight of an organic acid selected from one or both of tartaric acid and citric acid, and 0.1% to 5% by weight of liquid paraffin; A solid pharmaceutical formulation wherein the active ingredient comprises from 0.01% to 30% by weight of said formulation.

5. 5. The solid pharmaceutical formulation of claim 4, The solid pharmaceutical formulation, wherein the solid blend composition (2) comprises 90.5% by weight to 92.0% by weight of sorbitol, 5.0% by weight to 9.0% by weight of an organic acid selected from one or both of tartaric acid and citric acid, and 0.5% by weight to 3.5% by weight of liquid paraffin.

6. 5. The solid pharmaceutical formulation according to claim 4, wherein the formulation comprises 37.5% to 42.5% by weight of the lyophilized granules (1), 57.5% to 62.5% by weight of the solid blend composition (2), and 0.0% to 5.0% by weight of one or more pharmaceutically acceptable excipients as further components of the formulation, and the active ingredient constitutes 10% to 20% by weight of the formulation.

7. 7. The solid pharmaceutical formulation according to claim 6, wherein the formulation consists of 37.5% to 42.5% by weight of the freeze-dried granules (1) and 57.5% to 62.5% by weight of the solid blend composition (2), wherein the solid blend composition (2) consists of 90.5% to 92.0% by weight of sorbitol, 5.0% to 9.0% by weight of an organic acid selected from one or both of tartaric acid and citric acid, and 0.5% to 3.5% by weight of liquid paraffin.

8. 10. The solid pharmaceutical formulation of claim 1, wherein the active ingredient is sildenafil citrate.

9. 5. The solid pharmaceutical formulation of claim 4, wherein the organic acid is tartaric acid.

10. 10. The solid pharmaceutical formulation of claim 1, which is a free-flowing formulation.

11. 2. The solid pharmaceutical formulation according to claim 1, wherein the lyophilized granules (1) contain a base, preferably sodium hydroxide.

12. 2. The solid pharmaceutical formulation of claim 1, A solid pharmaceutical formulation, wherein the freeze-dried granules (1) comprise 35% to 46% by weight of sildenafil or a pharmaceutically acceptable salt thereof, 39% to 65% by weight of a sugar alcohol, and 0% to 15% by weight of a base.

13. 12. The solid pharmaceutical formulation of claim 11, A solid pharmaceutical formulation, wherein the weight ratio of the organic acid in said solid blend composition (2) to the base in said lyophilized granules (1) is at least 1.6:1, preferably at least 2:

1.

14. A package containing the formulation according to any one of claims 1 to 13.

15. 15. The packaging of claim 14, selected from the group consisting of sachets and stick packs.

16. A solid blend composition comprising sorbitol and liquid paraffin for use in the manufacture of the pharmaceutical formulation according to any one of claims 1 to 13.

17. A process for producing the pharmaceutical formulation according to any one of claims 1 to 13, comprising: (a) forming lyophilized granules (1) by sublimating a solvent from a preparation comprising sildenafil or a pharmaceutically acceptable salt thereof and a solvent; (b) forming a solid blend composition (2) comprising or consisting of sorbitol, liquid paraffin, and an organic acid selected from one or both of tartaric acid and citric acid; and (c) mixing the freeze-dried granules (1) obtained in step (a) with the solid blend composition (2) obtained in step (b); The process includes:

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