Pharmaceutical composition comprising guanfacine and method for producing the same

Abstract

To provide a pharmaceutical composition that achieves both dissolution stability and formulation stability of a guanfacine-containing preparation.SOLUTION: The present invention provides a pharmaceutical composition comprising guanfacine having the following formula or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable inorganic acid. Addition of the pharmaceutically acceptable inorganic acid achieves enhancement of stability of guanfacine or a pharmaceutically acceptable salt thereof, resulting in a stable tablet. The present invention further provides a method for preparing the pharmaceutical composition.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to pharmaceutical compositions and methods for their preparation, in particular pharmaceutical compositions comprising guanfacine. [Background technology]

[0002] Currently, pharmaceutical compositions treat central nervous system irritation by increasing brain concentrations through inhibition of reuptake of norepinephrine and dopamine. Selective norepinephrine reuptake inhibitors (NRIs); norepinephrine and dopamine reuptake inhibitors (NDRIs); tricyclic antidepressants (TCAs) regulate neurotransmitters in the brain, leading to accumulation of monoamines such as serotonin and norepinephrine (Non-Patent Document 1). Alpha 2 adrenergic agonists can enhance memory and executive function by increasing blood flow to the prefrontal cortex (Non-Patent Document 2).

[0003] Guanfacine is a selective alpha-adrenergic receptor agonist used as adjunctive therapy for ADHD in adults and children, and also for the treatment of hypertension. There has been no association between guanfacine and serum enzyme elevations or significant acute liver damage during treatment. In clinical trials, immediate release forms of guanfacine are commonly used to treat hyperactive, impulsive, or disruptive behavior. Guanfacine is primarily metabolized by the CYP3A4 enzyme. Many drugs may interact with guanfacine, and studies with the epilepsy drug phenobarbital, the antifungal drug ketoconazole, and the broad-spectrum antibiotic rifampicin have shown changes in pharmacokinetic parameters related to induction and inhibition of guanfacine metabolism. Lisdexamfetamine dimesylate (LDX) may slightly inhibit the metabolism of guanfacine, resulting in a 9% increase in guanfacine concentrations. There are also case reports indicating that guanfacine may increase the bioavailability of valproate. Studies have shown that the use of rifampicin for 8 days or ketoconazole for 3 days significantly affects the single-dose clearance of guanfacine. Furthermore, the guanfacine dose should be increased 5-fold when coadministered with phenobarbital. Pharmacokinetic recommendations suggest that the guanfacine dose should be doubled when coadministered with a CYP3A4 inducer and halved when a CYP3A4 inhibitor is added. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Cavaliere, F. et al, (2019) Sci Rep. 2019 Mar 19; 9(1):4881. doi: 10. [Non-Patent Document 2] Chang Gung Journal of Pharmacy Vol.18 No.4 2011 Summary of the Invention [Problem to be solved by the invention]

[0005] However, the formulations containing guanfacine have poor dissolution stability and formulation stability, so the application of guanfacine is limited. For example, in terms of dissolution stability, when different weights of organic acid are added to low-dose formulations, the dissolution changes significantly, and the change in dissolution is even more significant when the proportion of water in the human body is high. Furthermore, from the observation of high-dose formulations under forced conditions, the initial impurities of organic acid formulations are relatively large, which may affect the stability of formulations containing guanfacine. Therefore, how to balance the dissolution stability and formulation stability of formulations containing guanfacine is a challenging issue in the pharmaceutical field. [Means for solving the problem]

[0006] The present invention provides a pharmaceutical composition comprising guanfacine or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable inorganic acid, which addresses the poor dissolution and formulation stability problems faced by current guanfacine formulations. The guanfacine has the formula: [ka]

[0007] In one embodiment of the invention, the inorganic acid is selected from the group consisting of phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium bisulfite, sodium metabisulfite and boric acid.

[0008] In one embodiment of the invention, the content of said inorganic acid does not exceed 30% by weight of the pharmaceutical composition.

[0009] In one embodiment of the present invention, the content of said inorganic acid is from 2.5% to 27% by weight of the pharmaceutical composition.

[0010] In one embodiment of the present invention, the pharmaceutical composition comprises an enteric coating agent, and the content of the enteric coating agent is 20% or less by weight or 50% or less by weight of the pharmaceutical composition.

[0011] In one embodiment of the invention, the pharmaceutical composition comprises an excipient, the excipient being selected from the group consisting of microcrystalline cellulose, lactose (e.g., lactose hydrate), D-mannitol, sucrose, corn starch, calcium phosphate, sorbitol, and light anhydrous silicic acid.

[0012] In one embodiment of the invention, the pharmaceutical composition comprises an excipient selected from the group consisting of microcrystalline cellulose or lactose excipients.

[0013] In one embodiment of the invention, the pharmaceutical composition comprises a binder selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, N-vinylpyrrolidone, vinyl acetate, pregelatinized starch, gelatin, agar, and gum arabic.

[0014] In one embodiment of the invention, the binder is hydroxypropyl methylcellulose having a viscosity of 80 to 140,000 mPa·s.

[0015] In one embodiment of the invention, the pharmaceutical composition comprises a lubricant selected from the group consisting of talc, kaolin, titanium dioxide, magnesium stearate, calcium stearate, stearic acid, light anhydrous silicic acid, finely divided silicon dioxide, sodium stearyl fumarate and glycerol fatty acid esters.

[0016] In one embodiment of the present invention, the lubricant is a glycerol fatty acid ester.

[0017] In one embodiment of the invention, the pharmaceutical composition comprises a disintegrant selected from the group consisting of crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose, calcium carboxymethylcellulose, and potato starch.

[0018] In one embodiment of the present invention, the disintegrant is crospovidone.

[0019] In one embodiment of the invention, the pharmaceutical composition is in the form of a tablet.

[0020] The present invention also provides a method for preparing a pharmaceutical composition, the pharmaceutical composition comprising guanfacine or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable inorganic acid, which is prepared by mixing, optionally granulating if necessary, final mixing, and tableting. Effect of the Invention

[0021] The present invention has found for the first time that the dissolution stability and formulation stability can be improved by adding a specific inorganic acid to a pharmaceutical composition containing guanfacine or a pharma- ceutically acceptable salt thereof.Therefore, one aspect of the present invention is to provide a novel pharmaceutical composition containing guanfacine or a pharma- ceutically acceptable salt thereof, which has improved dissolution stability and formulation stability, and a tablet containing said pharmaceutical composition.Furthermore, another aspect of the present invention is to provide a method for producing a pharmaceutical composition containing guanfacine or a pharma- ceutically acceptable salt thereof, which has improved dissolution stability and formulation stability. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 is a comparative graph showing the results of a dissolution test for tablets produced by changing the ratio of organic acid in Comparative Example 1, Comparative Example 2, and Comparative Example 3. [Diagram 2] FIG. 2 is a comparative diagram showing the results of a comparative dissolution test of tablets produced by changing the ratio of organic acid in Examples 1, 2, and 3 of the present invention. [Diagram 3] FIG. 1 is a comparative diagram showing the results of a dissolution test of tablets produced by changing the ratio of organic acid in Example 4 and Example 5 of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] A detailed description of the technical solution of the present invention is provided below in conjunction with the accompanying drawings. It should be understood that the specific embodiments described in this specification are for the purpose of illustrating the present invention, and do not limit the scope of the present invention. The scope of the present invention is not limited by these embodiments, but is determined by the scope of the patent application.

[0024] The preparation method used in the present invention, such as Comparative Examples 1 to 3 and Examples 1 to 5, is a method that includes sieving all raw materials through a 40 mesh sieve, mixing them in a mixer, and finally adding a lubricant sieved through a 40 mesh sieve and compressing them into tablets. The compression pressure in this manufacturing method can be appropriately adjusted depending on the formulation and tablet shape, and is preferably in the range of 4 to 14 kN.

[0025] The dissolution test used in the present invention evaluates the dissolution results of the pharmaceutical compositions or tablets prepared in the low dose examples and comparative examples. Specifically, the tablets containing the pharmaceutical compositions are subjected to a dissolution test using a dissolution tester under the following conditions: 37°C water, 900 mL, paddle 50 rpm. The sample solution is then analyzed using HPLC under the following conditions: a mobile phase consisting of a mixture of aqueous sodium carbonate solution with pH adjusted with sodium hydroxide and acetonitrile, a C18 column with an inner diameter of 4.6 mm and a length of 15 cm, controlled at 27°C, and UV detection at a wavelength of 220 nm.

[0026] The stability test used in the present invention evaluates the impurity results of the pharmaceutical composition or tablet prepared in the high dose example and comparative example. Specifically, the tablet containing the pharmaceutical composition is subjected to the stability test under the following conditions: 40°C / 75% RH. Then, the sample solution is analyzed using HPLC under the following conditions: a mobile phase consisting of a mixture of sodium bicarbonate and tetrabutylammonium phosphate, pH adjusted with sodium hydroxide, and acetonitrile, a C18 column with an inner diameter of 4.6 mm and a length of 15 cm, controlled at 27°C, and UV detection at a wavelength of 220 nm.

[0027] Other ingredients that may be used in the present invention include excipients, binders, lubricants, disintegrants, surfactants, plasticizers, colorants, and other pharma- ceutically acceptable ingredients.

[0028] The excipient used in the present invention is, for example, crystalline cellulose or lactose (eg, lactose hydrate), D-mannitol, sucrose, corn starch, calcium phosphate, sorbitol, light anhydrous silicic acid, etc., with crystalline cellulose and lactose being preferred.

[0029] Binders used in the present invention are, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose (also known as hypromellose), povidone, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, N-vinylpyrrolidone and vinyl acetate, pregelatinized starch, gelatin, agar and gum arabic, with hypromellose being preferred. Preferably, hypromellose with a viscosity of 80-140,000 mPa·s, such as hypromellose 2208 (Methocel® K4M Premium CR, viscosity: 2500-5000 mPa·s, is used.

[0030] The lubricants used in the present invention include, for example, talc, kaolin, titanium dioxide, magnesium stearate, calcium stearate, stearic acid, light anhydrous silicic acid, finely ground silicon dioxide, sodium stearyl fumarate, and glycerin fatty acid esters, with glycerin fatty acid esters being preferred.

[0031] The disintegrant used in the present invention is, for example, crospovidone, low-substituted hydroxypropylcellulose, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose, calcium carboxymethylcellulose, potato starch, etc., with crospovidone being preferred.

[0032] The tablet formulations of Comparative Examples 1, 2 and 3 are shown in Table 1.

[0033] [Table 1]

[0034] The preparation method is as follows. 1. Ingredients: Guanfacine hydrochloride (active pharmaceutical ingredient), fumaric acid (organic acid) and Eudragit L100-55 (enteric coating agent) are weighed according to the formula. Other ingredients: for example, 13% to 50% binder, not more than 5% disintegrant, and 10% to 70% excipients. The above ingredients are sieved through a 40 mesh sieve.

[0035] 2.Mixing: 2.1 Guanfacine hydrochloride, fumaric acid, enteric coating agent Eudragit L100-55, excipients, binders and disintegrants are mixed uniformly and then granulated as necessary. Then, 12% to 15% by weight of lubricant sieved through a 40 mesh sieve is slowly added.

[0036] 3.Tablet compression: The tablets are compressed according to the weight determined in the intermediate test. A circular 7.0 mm punch is used for compression, the hardness is 4N-14N, and the weight difference is ±5%.

[0037] The tablet formulations of Examples 1, 2 and 3 are shown in Table 2.

[0038] [Table 2]

[0039] The preparation method is as follows. 1. Ingredients: Guanfacine hydrochloride, sodium bisulfite (inorganic acid), Eudragit L100-55 (enteric coating agent) are weighed according to the formula. Other ingredients: for example, 13% to 50% binder, not more than 5% disintegrant, and 10% to 70% excipients. The above ingredients are sieved through a 40 mesh sieve.

[0040] 2.Mixing: 2.1 Guanfacine hydrochloride, sodium bisulfite, enteric coating agent Eudragit L100-55, excipients, binders and disintegrants are mixed uniformly and then granulated as necessary. Then, 12% to 15% by weight of lubricant sieved through a 40 mesh sieve is slowly added.

[0041] 3.Tablet compression: The tablets are compressed according to the weight determined in the intermediate test. A circular 7.0 mm punch is used for compression, the hardness is 4N-14N, and the weight difference is ±5%.

[0042] The tablet formulations of Examples 4 and 5 are shown in Table 3.

[0043] [Table 3]

[0044] The preparation method is as follows. 1. Weigh out the ingredients: guanfacine hydrochloride, boric acid (inorganic acid), and Eudragit L100-55 (enteric coating agent) according to the formula. Other ingredients: for example, 13% to 50% binder, not more than 5% disintegrant, and 10% to 70% excipients. The above ingredients are sieved through a 40 mesh sieve.

[0045] 2.Mixing: 2.1 Guanfacine hydrochloride, boric acid, enteric coating agent Eudragit L100-55, excipients, binders and disintegrants are mixed uniformly and then granulated as necessary. Then, 12% to 15% by weight of lubricant sieved through a 40 mesh sieve is slowly added.

[0046] 3.Tablet compression: The tablets are compressed according to the weight determined in the intermediate test. A circular 7.0 mm punch is used for compression, the hardness is 4N-14N, and the weight difference is ±5%.

[0047] 4. Dissolution test using HPLC Analysis conditions: (1) Column: C18, length x inner diameter 15 cm x 4.6 mm. (2) Mobile phase: Isocratic elution with a mixture of aqueous sodium bicarbonate and acetonitrile (adjusted to pH 10 with sodium hydroxide). (3) Injection volume: 20μL. (4) Flow rate: 1.2mL / min. (5) Temperature: 27℃ (6) Detection wavelength: UV 220nm.

[0048] Impurity testing using HPLC Analysis conditions: (1) Column: C18, length x inner diameter 15 cm x 4.6 mm. (2) Mobile phase: Isocratic elution with a mixture of sodium bicarbonate / tetra-n-butylammonium hydrogen phosphate and acetonitrile (adjusted to pH 10 with sodium hydroxide). (3) Injection volume: 100μL. (4) Flow rate: 1mL / min. (5) Temperature: 27℃ (6) Detection wavelength: UV 220nm.

[0049] The dissolution test method was in accordance with the Pharmacopoeia standard, the solvent was water at 37°C, the volume was 900 mL, and the rotation speed was 50 rpm. Sampling for analysis was performed at 4, 8, 12, and 24 hours.

[0050] The dissolution curves of the tablets in the Examples and Comparative Examples in the dissolution test will be described with reference to Figures 1 to 3.

[0051] The dissolution profiles of the tablets of Comparative Examples 1, 2 and 3 at 37° C. are examined. The experimental results are shown in FIG.

[0052] From the dissolution test data shown in FIG. 1, in the comparative example of the present invention, the tablet prepared using fumaric acid as an organic acid additive was found to release the active ingredient in water for more than 24 hours, and confirmed whether the mass of the pharmaceutical composition was stable over time. The experimental results show that when 1 mg of low-dose organic acid fumaric acid was added, the release was 35.17% in 4 hours, reached 44.43% in 12 hours, and stabilized in 24 hours. When 3 mg of medium-dose organic acid fumaric acid was added, the release was 36.40% in 4 hours, reached 51.33% in 8 hours, and 57.07% in 24 hours. When 7.5 mg of high-dose organic acid fumaric acid was added, the release was 45.05% in 4 hours, reached 65.45% in 8 hours, 73.95% in 12 hours, and 80.95% in 24 hours. From these experimental results, it is clear that increasing the organic acid concentration increases the release of the tablet in water, and even a small increase in the organic acid concentration has a significant effect on the release rate of the tablet, especially when taken with water. Therefore, tablets containing organic acids in the formulation tend to show erratic drug release, which affects bioavailability, etc.

[0053] [Table 4]

[0054] The dissolution test curves of the tablets of Example 1, Example 2 and Example 3 at 37° C. are examined. The experimental results are shown in FIG.

[0055] From the dissolution test data shown in FIG. 2, in the comparative example of the present invention, the tablet prepared using sodium bisulfite as an inorganic acid additive was found to release the active ingredient in water for more than 24 hours, and confirmed whether the mass of the pharmaceutical composition was stable over time. The experimental results show that when 7.5 mg of a low dose of inorganic acid sodium bisulfite was added, the release was 22.80% in 4 hours, 31.65% in 12 hours, and 39.60% in 24 hours. When 20 mg of a medium dose of inorganic acid sodium bisulfite was added, the release was 19.40% in 4 hours, 25.65% in 8 hours, and 39.10% in 24 hours. When 40 mg of a high dose of inorganic acid sodium bisulfite was added, the release was 19.45% in 4 hours, 27.15% in 8 hours, 32.00% in 12 hours, and 51.30% in 24 hours. From these experimental results, compared with the comparative example, the examples with different ratios of inorganic acid sodium bisulfite achieved a good and stable release rate. Therefore, this formulation design can improve the stability of the process during tablet production, reduce the variability of tablet release in the body when ingested by a patient, and achieve advantages over organic acid formulations both during production and in vivo.

[0056] [Table 5]

[0057] The dissolution test curves of the tablets of Example 4 and Example 5 at 37° C. are examined. The experimental results are shown in FIG.

[0058] From the dissolution test data in FIG. 3, the tablet prepared in the present invention with boric acid as an inorganic acid additive exhibited release of active ingredient in water for more than 24 hours, and confirmed whether the mass of the pharmaceutical composition was stable over time. According to the experimental results, when a low dose of 3.75 mg of boric acid was added, the release was 23.05% at 4 hours, 26.70% at 8 hours, 28.10% at 12 hours, and 28.80% at 24 hours. Similarly, when a high dose of 7.5 mg of boric acid was added, the release was 26.70% at 4 hours, 30.30% at 8 hours, 31.30% at 12 hours, and 32.85% at 24 hours. These experimental results show that, compared with the comparative example, Example 4 and Example 5 achieve similar stable release rates by using different proportions of boric acid as an inorganic acid additive. Therefore, this formulation design can improve the stability of the manufacturing process during tablet production and reduce the variability of the tablet's release in the body when administered to a patient, providing advantages over organic acid formulations both during manufacturing and in vivo.

[0059] [Table 6]

[0060] Stability tests were carried out to evaluate the impurity results of the pharmaceutical compositions or tablets prepared in the high dose examples and comparative examples. Specifically, the stability experiments of the comparative examples and examples were carried out under the forced conditions of 40°C / 75%RH, and the experimental results are shown in Table 7.

[0061] The USP Pharmacopoeia test specifications state that the impurity of 2,6-dichlorophenylacetic acid is less than 1.0%, peak 1 (unspecified decomposition product) is less than 0.5%, and all impurities (total impurities) are less than 1.5%. This is used to evaluate impurities and decomposition products that occur during storage. The tablets prepared in the comparative example initially had 0.1% 2,6-dichlorophenylacetic acid, 0.2% peak 1, and 0.3% all impurities. After one month, the impurities were 0.1% 2,6-dichlorophenylacetic acid, 0.2% peak 1, and 0.3% all impurities. After three months, the impurities were 0.2% 2,6-dichlorophenylacetic acid, 0.2% peak 1, and 0.4% all impurities. As a result of the experiment, the tablets prepared in the comparative example containing organic acid additives were destroyed under high temperature and humidity conditions, and the samples became unstable. The tablets prepared in the examples initially contained 0.1% 2,6-dichlorophenylacetic acid, no peak 1 was detected, and all impurities were 0.1%. The experimental results showed that the tablets prepared in the examples containing inorganic acid additives were more stable than the tablets in the comparative examples under high temperature and humidity conditions, and the quality of the pharmaceutical composition was stable regardless of changes in time, temperature, and humidity.

[0062] [Table 7]

[0063] (Additional Note) (Appendix 1) A pharmaceutical composition comprising guanfacine or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable inorganic acid.

[0064] (Appendix 2) 2. The pharmaceutical composition of claim 1, wherein the inorganic acid is selected from the group consisting of phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium bisulfite, sodium metabisulfite, and boric acid.

[0065] (Appendix 3) 2. The pharmaceutical composition according to claim 1, wherein the content of the inorganic acid is 30% by weight or less of the pharmaceutical composition.

[0066] (Appendix 4) 2. The pharmaceutical composition according to claim 1, wherein the content of the inorganic acid is from 2.5% to 27% by weight of the pharmaceutical composition.

[0067] (Appendix 5) 2. The pharmaceutical composition of claim 1, further comprising an enteric coating agent, wherein the content of the enteric coating agent is 20% by weight or less or 50% by weight or less of the pharmaceutical composition.

[0068] (Appendix 6) 2. The pharmaceutical composition of claim 1, further comprising an excipient selected from the group consisting of crystalline cellulose, lactose, D-mannitol, sucrose, corn starch, calcium phosphate, sorbitol, and light anhydrous silicic acid.

[0069] (Appendix 7) 2. The pharmaceutical composition of claim 1, comprising a binder selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose, polyvinylpyrrolidone, N-vinylpyrrolidone, vinyl acetate, pregelatinized starch, gelatin, agar, and gum arabic.

[0070] (Appendix 8) 2. The pharmaceutical composition of claim 1, further comprising a lubricant selected from the group consisting of talc, kaolin, titanium dioxide, magnesium stearate, calcium stearate, stearic acid, light anhydrous silicic acid, finely divided silicon dioxide, sodium stearyl fumarate, and glycerol fatty acid esters.

[0071] (Appendix 9) 2. The pharmaceutical composition of claim 1, in the form of a tablet.

[0072] (Appendix 10) 2. A method for preparing the pharmaceutical composition according to claim 1, comprising mixing guanfacine or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable inorganic acid, optionally granulating, final mixing and tablet compression.

Claims

1. A pharmaceutical composition comprising guanfacine or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable inorganic acid.

2. 2. The pharmaceutical composition of claim 1, wherein the inorganic acid is selected from the group consisting of phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium bisulfite, sodium metabisulfite and boric acid.

3. The pharmaceutical composition according to claim 1 , wherein the content of the inorganic acid is 30% by weight or less of the pharmaceutical composition.

4. The pharmaceutical composition according to claim 1 , wherein the content of the inorganic acid is from 2.5% to 27% by weight of the pharmaceutical composition.

5. 2. The pharmaceutical composition of claim 1, comprising an enteric coating agent, the content of the enteric coating agent being 20% ​​by weight or less or 50% by weight or less of the pharmaceutical composition.

6. 2. The pharmaceutical composition of claim 1, comprising an excipient selected from the group consisting of crystalline cellulose, lactose, D-mannitol, sucrose, corn starch, calcium phosphate, sorbitol and light anhydrous silicic acid.

7. 2. The pharmaceutical composition of claim 1, comprising a binder selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, N-vinylpyrrolidone, vinyl acetate, pregelatinized starch, gelatin, agar, and gum arabic.

8. 2. The pharmaceutical composition of claim 1, further comprising a lubricant selected from the group consisting of talc, kaolin, titanium dioxide, magnesium stearate, calcium stearate, stearic acid, light anhydrous silicic acid, finely divided silicon dioxide, sodium stearyl fumarate and glycerol fatty acid esters.

9. 10. The pharmaceutical composition of claim 1 in the form of a tablet.

10. 2. A method for preparing the pharmaceutical composition according to claim 1, comprising blending guanfacine or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable inorganic acid, optionally granulating, final blending and tablet compression.

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