Sildenafil pharmaceutical formulations

Abstract

Disclosed is a solid pharmaceutical formulation comprising a mixture of (1) lyophilized particles comprising sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient and (2) a non-lyophilized composition wherein the formulation comprises from 35% to 50% by weight of the lyophilized particles (1) and is dissolved in the oral cavity, and the non-lyophilized composition (2) is a solid blend composition comprising a flow enhancer; a package containing the formulation; and a method for manufacturing the formulation.

Description

Technical Field

[0001] The present invention relates to solid pharmaceutical formulations of sildenafil or a pharmaceutically acceptable salt thereof, methods for preparing the same, and solid blend compositions for making the same. Background Art

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

[0003] Fast dissolving dosage forms are typically prepared using a multi-step process. Some of these processes utilize a freeze-drying step in which the solvent is removed from a solution and / or suspension comprising the pharmaceutically active substance, a carrier material, and a solvent.

[0004] Pharmaceutical formulations manufactured by lyophilization have various advantages, but also present various challenges, such as free flow, hygroscopicity, bitter taste, dose uniformity, content uniformity, and pharmacokinetics. The present invention aims to overcome these challenges. Summary of the Invention

[0005] The present invention provides a novel blend composition of sorbitol and liquid paraffin for improving various formulation characteristics of pharmaceutical formulations, namely, flow properties, moisture resistance, antistatic properties, and compressibility (Carr's index). The blend composition also contains tartaric acid and / or citric acid, and is particularly useful for improving the dissolution characteristics of pharmaceutical formulations containing sildenafil.

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

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

[0008] The present invention also provides a method for producing the solid pharmaceutical formulation of the present invention, the method comprising:

[0009] (a) forming freeze-dried particles (1) by subliming a solvent from a formulation comprising sildenafil or a pharmaceutically acceptable salt thereof and a solvent;

[0010] (b) forming a solid blend composition (2), the solid blend composition comprising or consisting of sorbitol, liquid paraffin, and one or two organic acids selected from tartaric acid and citric acid; and

[0011] (c) mixing the solid blend composition (2) obtained in step (b) with the freeze-dried particles (1) obtained in step (a). BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 The formulations of Examples 1 to 4 were compared with commercially available products. Dissolution rate of 100 mg tablets in water.

[0013] Figure 2 The formulations of comparative examples A to D were compared with commercially available products. Dissolution rate of 100 mg tablets in water.

[0014] Figure 3 is a photograph of a stick pack of the present invention. DETAILED DESCRIPTION

[0015] The pharmaceutical formulation of the present invention dissolves in the oral cavity and comprises 35% to 50% by weight of lyophilized particles (1) and a non-lyophilized composition (2) which is a solid blend composition comprising a flow enhancer.

[0016] In one embodiment, the formulation provides at least one of the following pharmacokinetic parameters after oral administration to a human subject: an AUC (0-10 min) of at least 3.5 ng·h / mL; and an AUC (0-30 min) of at least 150 ng·h / mL. The AUC values are determined as further described in the experimental section.

[0017] The flow enhancer in the solid blend composition (2) is preferably represented by a combination of sorbitol and liquid paraffin.

[0018] 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 particles (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 additional components of the formulation, and 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. The solid blend composition (2) preferably 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.

[0019] The formulation preferably comprises 10% to 20% by weight of the active ingredient, 37.5% to 42.5% by weight of the lyophilized particles (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 additional constituents of the formulation.

[0020] In one embodiment, the formulation consists of 37.5% to 42.5% by weight of the freeze-dried particles (1) and 57.5% to 62.5% by weight of the solid blend composition (2), and 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.

[0021] In one embodiment, the active ingredient of the formulation of the present invention is sildenafil citrate.

[0022] In one embodiment, the organic acid is tartaric acid.

[0023] In one embodiment, the solid pharmaceutical formulation is a free-flowing formulation.

[0024] The freeze-dried particles (1) contain sildenafil or a pharmaceutically acceptable salt thereof, and may optionally contain additional pharmaceutically acceptable excipients, particularly those conventionally used in the method for producing freeze-dried particles. Pharmaceutically acceptable excipients may be selected from sugars, sugar alcohols, monosaccharides, disaccharides, trisaccharides, polysaccharides, proteins, amino acids, gums, and the like, including but not limited to mannitol, trehalose, raffinose, inositol, pullulan, sucrose, lactose, glucose (dextrose), erythritol, xylitol, lactitol, maltitol, isomalt, alanine, arginine, threonine, glycine, cysteine, serine, histidine, valine, proline, lysine, asparagine, glutamine, ribose, glucose (glucose), galactose, fructose, maltose, maltotriose, guar gum, xanthan gum, tragacanth gum, veegum, and the like. Typically, the freeze-dried particles (1) do not contain paraffin. In one embodiment of the present invention, the freeze-dried particles (1) further comprise a base, such as one or more selected from the group consisting of sodium hydroxide, potassium hydroxide, magnesium hydroxide, aluminum hydroxide and calcium hydroxide, preferably sodium hydroxide.

[0025] In one embodiment of the present invention, the freeze-dried particles (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 an alkali (preferably sodium hydroxide). More preferably, the freeze-dried particles (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 an alkali (preferably sodium hydroxide). The proportion of the alkali is preferably selected so that the weight ratio of the organic acid in the solid blend composition (2) to the alkali in the freeze-dried particles (1) is at least 1.6:1, preferably at least 2:1. There is no specific upper limit to the weight ratio of the organic acid to the alkali. It can be up to 10:1, or up to 5:1.

[0026] The solid blend composition (2) preferably 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. The solid blend composition (2) more preferably 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. Typically, the solid blend composition (2) does not contain an active ingredient.

[0027] In addition to components (1) and (2) discussed above, the formulation may also contain other excipients (adjuvants, auxiliary agents), such as, but not limited to, fillers, thickeners (including but not limited to guar gum and xanthan gum), binders, diluents, lubricants, pH adjusters, protective agents, viscosity enhancers, wicking agents, non-effervescent disintegrants, effervescent disintegrants, surfactants, antioxidants, wetting agents, colorants, flavorings, taste masking agents, sweeteners, preservatives, etc.

[0028] In an embodiment of the present invention, the formulation is obtained by the method of the present invention, which comprises the steps of forming a solid blend composition (2) by blending sorbitol, liquid paraffin and one or two organic acids selected from tartaric acid and citric acid, and adding the solid blend composition (2) to the active ingredient in the form of freeze-dried particles (1).

[0029] 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 manufacture of a pharmaceutical formulation comprising 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 one or both of tartaric acid and citric acid. In one embodiment, the blend composition consists of the indicated components in the indicated preferred and more preferred proportions.

[0030] The present invention also provides a method for producing the solid pharmaceutical formulation of the present invention, the method comprising:

[0031] (a) forming lyophilized particles (1) by subliming a solvent from a formulation comprising sildenafil or a pharmaceutically acceptable salt thereof and a solvent and optionally a base;

[0032] (b) forming a solid blend composition (2), the solid blend composition comprising or consisting of sorbitol, liquid paraffin, and one or two organic acids selected from tartaric acid and citric acid;

[0033] (c) mixing the solid blend composition (2) obtained in step (b) with the freeze-dried particles (1) obtained in step (a).

[0034] The blend composition of sorbitol and liquid paraffin (2) is mixed with the freeze-dried particles (1) by methods known in the art such as geometric mixing or mixing using any type of mixer.

[0035] The process of the present invention allows obtaining a solid pharmaceutical formulation in the form of free-flowing granules, which is a preferred embodiment of the present invention.

[0036] The preferred proportions of the active ingredient, sorbitol, liquid paraffin, organic acid and solid blend composition in the method of the present invention, as well as the preferred types and proportions of the optional additional pharmaceutically acceptable excipients (particularly base) are the same as those in the pharmaceutical formulation of the present invention.

[0037] The solvent used in the formulation to be lyophilized, comprising the active ingredient and optionally further pharmaceutically acceptable excipients such as sugar alcohols and bases, is generally water.

[0038]

[0014] Herein, the terms "active ingredient" and "pharmaceutically active ingredient" are used interchangeably.

[0039] A suitable route of administration for the dosage form of the present invention is oral administration.

[0040] In one embodiment, the pharmaceutical formulation of the present invention may be administered to a patient in the form of particles.

[0041] In another aspect, the pharmaceutical formulation of the present invention is packaged in a package for dispensing single doses of the formulation, also referred to as a unit dosage form. Non-limiting examples of a package / unit dosage form are a sachet or a strip pack.

[0042] In another embodiment, the pharmaceutical formulation of the present invention (e.g., in the form of granules) is packaged as a multi-dose form, i.e., a dosage form that allows the withdrawal of multiple doses of any size. Non-limiting examples of multi-dose forms are bottles and any other container capable of holding granules.

[0043] A patient taking the free-flowing granular formulation of the present invention will be sure that he has received the entire dose, ie that there is no residue in the packaging / unit dosage form.

[0044] In one embodiment, oral administration is performed by emptying the sachet, stick pack or (any other) unit pack containing the granules onto the tongue and swallowing the contents.

[0045] In another embodiment, oral administration is performed by dissolving the particles in a solvent (eg, a glass of water) and then drinking the solution.

[0046] The exact dosage and administration regimen of the dosage form will depend on the therapeutic effect to be achieved and may vary with the route of administration and the age and condition of the individual subject to whom the formulation is to be administered. Sometimes, a patient may be instructed to take two or any other number of unit dosage forms, such as a strip pack, in a single administration, or sometimes, to take only a portion of a unit dosage form, such as half or a quarter, in a single administration.

[0047] 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 following administration.

[0048] Examples

[0049] 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.

[0050] Materials and methods

[0051]

[0052] Example 1

[0053]

[0054]

[0055] Example 2

[0056]

[0057] Example 3

[0058]

[0059]

[0060] Example 4

[0061]

[0062] Manufacturing Process

[0063] I. Freeze-dried particles

[0064] 1. Dissolve sodium hydroxide in 370 mL of purified water while stirring with an overhead stirrer.

[0065] 2. While stirring, evenly disperse sildenafil citrate in the solution of step 1.

[0066] 3. Homogenize the dispersion obtained in step 2 using a homogenizer and an overhead stirrer.

[0067] 4. Dissolve hydroxypropylcellulose L in water (166.5 g) and add this solution to the dispersion from step 2 with stirring.

[0068] 5. Add mannitol to the dispersion.

[0069] 6. Bring the final weight of the solution / dispersion to 1200 g using purified water.

[0070] 7. Continue mixing the solution / dispersion using a magnetic / overhead stirrer.

[0071] 8. The solution / dispersion was filled into stainless steel trays and freeze dried in a freeze dryer.

[0072] 9. After complete freeze drying, the lyophilized cake was sieved through a #40 mesh to obtain lyophilized granules.

[0073] II. Blend Composition

[0074] 10. Pass sorbitol through a #40 sieve and neotame and orange flavor through a #60 sieve. Mix the sieved sorbitol, neotame and orange flavor in a rapid mixing granulator.

[0075] 11. To the mixture from step-10 (80 g) add liquid paraffin dropwise and mix to obtain a uniformly distributed composition.

[0076] 12. Sieve the composition from step 11 through a #40 screen and mix with the mixture from step 10 using a rapid mixing granulator

[0077] 13. The mixture obtained in step 12 was passed through a 40# sieve and transferred to a double cone mixer.

[0078] 14. Add the organic acid to the mixer of step 13 and blend the mixture to obtain a blend composition

[0079] III. Preparations

[0080] 15. In a double cone mixer, mix the lyophilized granules from step 9 with the blend composition from step 14 to obtain a free-flowing sildenafil formulation.

[0081] 16. Fill the free-flowing formulation into stick packs and seal. A comparative pharmaceutical formulation was prepared essentially as described in Example 1 with the following changes: Comparative Example A

[0082]

[0083] Comparative Example B

[0084]

[0085]

[0086] Comparative Example C

[0087]

[0088] Comparative Example D

[0089]

[0090]

[0091] In vitro dissolution

[0092] In vitro dissolution testing was performed according to USP Type I, with a basket (100#) at 100 rpm in 900 mL of water (as dissolution medium), maintained at 37°C ± 0.5°C. The release profile of 100 mg tablets is as follows Figure 1 As shown. Comparative Examples A to D compared to The release profile of 100 mg tablets is as follows Figure 2 As shown. The formulations according to Examples 1 to 4 showed similar or faster release at 5 minutes compared to the 100 mg tablet.

[0093] Bioavailability of stable oral compositions

[0094] A two-way, randomized, crossover study was conducted to compare a 100 mg dose of Example 1 with a 100 mg dose of Example 1 in 48 healthy adult males under fasting conditions. Bioavailability of sildenafil citrate 100 mg film-coated tablets.

[0095] In 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 dosing. Dosing was completed as follows:

[0096] Example 1 containing 100 mg of sildenafil citrate was orally administered to volunteers without water.

[0097] Take a 100 mg oral dose with about 240 mL of water. tablet.

[0098] Sildenafil plasma concentrations were quantified by serial blood sampling and sildenafil pharmacokinetic (PK) parameters were determined by non-compartmental analysis. Parameters of interest included peak plasma concentration (Cmax), area under the plasma concentration curve (AUC), time to peak plasma concentration (Tmax), and time delay (Tlag) in the observed sildenafil concentrations. AUC was measured by the linear trapezoidal method.

[0099] result

[0100]

[0101] *The observed ranges of PK parameters are given in parentheses

[0102] Assessment 1: Bulk Density & Tap Density Results

[0103] Bulk density and tap density are important in understanding the flow properties of a formulation. The bulk density of a material is the ratio of the mass to the volume (including the void volume between the particles) of an untapped powder sample. The tap density is the increased bulk density obtained after mechanically tapping a container containing the powder sample. The tap density is obtained by mechanically tapping a graduated cylinder containing the sample until a small, almost no further volume change is observed. Because the interparticle interactions that affect the expansion properties of a powder are also the interactions that hinder powder flow, comparing bulk density and tap density can give a measure of the relative importance of these interactions in a given powder. This comparison is often used as an indicator of the flowability of a powder, such as the compressibility index or Hausner ratio:

[0104] Compression index (Carr index):

[0105]

[0106] Hausnaby:

[0107]

[0108] V0 = unstable apparent volume (total volume) V f = Final volume after compaction

[0109] The lower the values of the compressibility index and the Hausner ratio, the better the flow properties of the powder.

[0110] Procedure for determining bulk density:

[0111] According to the United States Pharmacopeia (USP) <616> For Method I, use a 100-mL graduated cylinder readable to 1 mL and an amount of powder so that its apparent untapped volume is between 50 and 100 mL.

[0112] Procedure for determining tap density:

[0113] According to the United States Pharmacopeia (USP) <616> Chapter Method I, details are as follows:

[0114] • Mount a 100-mL graduated cylinder (readable to 1 mL) weighing 130 ± 16 g on a holder weighing 240 ± 12 g.

[0115] Perform 10, 500 and 1250 taps on the powder sample and measure the corresponding volume V to the nearest scale unit 10 、V 500 and V 1250 .

[0116] If V 500 With V 1250 If the difference between them is less than or equal to 1mL, then V 1250 is the tapped volume.

[0117] If V 500 With V 1250 If the difference between the measured values exceeds 1 mL, the measurement is repeated with an increment of, for example, 1250 taps, until the difference between the subsequent measured values is less than or equal to 1 mL.

[0118] result

[0119]

[0120] Assessment 2: Angle of Repose:

[0121] The angle of repose is used to characterize the flow properties of solids. It is a property related to interparticle friction, or the resistance to motion between particles. The angle of repose is the constant three-dimensional angle (relative to the horizontal base) exhibited by a conical pile of material.

[0122] Procedure (according to USP General <1174> ):

[0123] The angle of repose is formed on a fixed base plate that has a retaining edge to retain a layer of powder on the base plate. The base plate should be free of vibration. The height of the funnel is varied to carefully accumulate a symmetrical powder cone. When moving the funnel, care should be taken to prevent vibration. When forming the powder pile, the funnel height should be kept at a distance of approximately 2-4 cm from the top of the powder pile to minimize the impact of falling powder on the tip of the cone. 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 calculating the angle of repose (a) by the following equation:

[0124] tan(a) = height / 0.5 base plate.

[0125] result

[0126]

[0127] Assessment 3: Moisture Content:

[0128] The drug formulations were placed in open Petri dishes, which were then placed in Climacels maintained at 25°C / 75% RH to simulate exposure to high humidity. The moisture content of each formulation was analyzed after 1, 2, and 6 hours in Climacels. Moisture content was assessed using the USP General Chapter 921 - Water method.

[0129] result

[0130]

[0131] Assessment 4: Anti-stick properties

[0132] The anti-stick properties of the formulations were measured by determining the residual content using the following procedure:

[0133] program:

[0134] Fill the drug preparation evenly into 10 Figure 3 The stick packs were filled into stick packs made of flexible laminate as shown. The fill weight of each stick pack was recorded for further reference. The filled stick packs were sealed using a sealer. The sealed stick packs were kept on a vibrating motion device for 30 minutes to trap the formulation in the corners of the stick packs. 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 measure the amount of formulation recovered from each stick pack. The residual content was calculated using the following formula:

[0135] (Fill weight of stick pack) - (Content recovered from stick pack) = Residual content

[0136] result

[0137]

Claims

1. A solid pharmaceutical formulation comprising a mixture of (1) lyophilized particles comprising 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 lyophilized particles (1) and dissolves in the oral cavity, and the non-lyophilized composition (2) is a solid blend composition comprising a flow enhancer.

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

3. The solid pharmaceutical preparation according to claim 1 or 2, wherein The flow enhancer is a combination of sorbitol and liquid paraffin.

4. The solid pharmaceutical preparation according to claim 3, wherein 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 additional constituents 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, and The active ingredient comprises 0.01% to 30% by weight of the formulation.

5. The solid pharmaceutical preparation according to claim 4, 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.

6. The solid pharmaceutical preparation according to claim 4 or 5, wherein The formulation comprises 37.5% to 42.5% by weight of the freeze-dried particles (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 additional constituents of the formulation, and the active ingredient accounts for 10% to 20% by weight of the formulation.

7. The solid pharmaceutical preparation according to claim 6, wherein The formulation consists of 37.5% to 42.5% by weight of the freeze-dried particles (1) and 57.5% to 62.5% by weight of the solid blend composition (2), and 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. The solid pharmaceutical formulation according to any one of claims 1 to 7, wherein The active ingredient is sildenafil citrate.

9. The solid pharmaceutical formulation according to any one of claims 4 to 8, wherein The organic acid is tartaric acid.

10. The solid pharmaceutical formulation according to any one of claims 1 to 9, which is a free-flowing formulation.

11. The solid pharmaceutical formulation according to any one of claims 1 to 10, wherein The freeze-dried particles (1) contain a base, preferably sodium hydroxide.

12. The solid pharmaceutical formulation according to any one of claims 1 to 11, wherein The freeze-dried particles (1) contain 35% to 46% by weight of sildenafil or a pharmaceutically acceptable salt thereof, 39% to 65% by weight of sugar alcohol, and 0% to 15% by weight of a base.

13. The solid pharmaceutical preparation according to claim 11 or 12, wherein The weight ratio of the organic acid in the solid blend composition (2) to the base in the freeze-dried particles (1) is at least 1.6:1, preferably at least 2:

1.

14. A package containing a formulation according to any one of the preceding claims.

15. The package of claim 14 selected from the group consisting of a pouch and a stick pack.

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

17. A method for producing a pharmaceutical formulation according to any one of claims 1 to 13, comprising: (a) forming freeze-dried particles (1) by subliming the solvent from a formulation comprising sildenafil or a pharmaceutically acceptable salt thereof and a solvent; (b) forming a solid blend composition (2), wherein the solid blend composition comprises or consists of sorbitol, liquid paraffin, and one or two organic acids selected from tartaric acid and citric acid; as well as (c) mixing the freeze-dried particles (1) obtained in step (a) with the solid blend composition (2) obtained in step (b).

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