JP7844541B2 - Pharmaceutical composition containing guanfacine and method for producing the same - Google Patents

Description

This invention relates to a pharmaceutical composition and a method for producing the same, and more particularly to a pharmaceutical composition containing guanfacine.

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

Guanfacine is a selective alpha-adrenergic receptor agonist used as an adjunctive therapy for ADHD in adults and children, and is also used to treat hypertension. During treatment, there is no association between guanfacine and elevated serum enzymes or marked acute liver injury. In clinical trials, immediate-release guanfacine is commonly used to treat hyperactivity, impulsivity, or destructive 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 associated with the induction and inhibition of guanfacine metabolism. Lisdexamfetamine dimesylate (LDX) may slightly inhibit the metabolism of guanfacine, resulting in a 9% increase in guanfacine concentration. There are also case reports suggesting that guanfacine may increase the bioavailability of valproate. Studies have shown that using rifampicin for 8 days or ketoconazole for 3 days significantly affects the single-dose clearance of guanfacine. Furthermore, when used in combination with phenobarbital, the guanfacine dose needs to be increased fivefold. Pharmacokinetic recommendations suggest doubling the guanfacine dose when used in combination with CYP3A4 inducers, and halving the guanfacine dose when adding a CYP3A4 inhibitor.

Cavaliere, F. et al, (2019) Sci Rep. 2019 Mar 19; 9(1):4881. doi: 10. Chang Gung Journal of Pharmacy Vol.18 No.4 2011

However, formulations containing guanfacine have poor dissolution stability and formulation stability, limiting the application of guanfacine. For example, in terms of dissolution stability, adding organic acids of different weights to low-dose formulations significantly alters dissolution, and this change becomes even more pronounced when the proportion of water in the human body is high. Furthermore, observations of high-dose formulations under forced conditions suggest that initial impurities in organic acid formulations are relatively high, potentially affecting the stability of guanfacine-containing formulations. Therefore, achieving both dissolution stability and formulation stability in guanfacine-containing formulations remains a challenging issue in the pharmaceutical field.

The present invention provides a pharmaceutical composition characterized by comprising guanfacine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable inorganic acid, thereby addressing the problems of poor dissolution stability and formulation stability faced by current guanfacine formulations. The guanfacine has the following formula:

In one embodiment of the present 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.

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

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

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

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

In one embodiment of the present invention, the pharmaceutical composition contains an excipient selected from the group consisting of crystalline cellulose or lactose excipients.

In one embodiment of the present invention, the pharmaceutical composition contains a binder selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, N-vinylpyrrolidone, vinyl acetate, pregelatinized starch, gelatin, agar, and gum arabic.

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

In one embodiment of the present invention, the pharmaceutical composition contains a lubricant selected from the group consisting of 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.

In one embodiment of the present invention, the lubricant is a glycerin fatty acid ester.

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

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

In one embodiment of the present invention, the pharmaceutical composition is in the form of a tablet.

Furthermore, the present invention provides a method for producing a pharmaceutical composition, the pharmaceutical composition comprising guanfacine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable inorganic acid, which are mixed, optionally granulated, finally mixed, and compressed into tablets.

This invention is the first to discover that the dissolution stability and formulation stability of a pharmaceutical composition containing guanfacine or a pharmaceutically acceptable salt thereof can be improved by adding a specific inorganic acid. Therefore, one aspect of the invention is to provide a novel pharmaceutical composition containing guanfacine or a pharmaceutically acceptable salt thereof with improved dissolution and formulation stability, and a tablet containing said pharmaceutical composition. Furthermore, another aspect of the invention is to provide a method for producing a pharmaceutical composition containing guanfacine or a pharmaceutically acceptable salt thereof with improved dissolution and formulation stability.

This is a comparative chart of the dissolution test results for tablets manufactured by varying the proportion of organic acids in Comparative Example 1, Comparative Example 2, and Comparative Example 3. This is a comparative chart of the dissolution test results for tablets manufactured by varying the proportion of organic acids in Examples 1, 2, and 3 of the present invention. This is a comparative chart of the dissolution test results for tablets manufactured by changing the proportion of organic acids in Examples 4 and 5 of the present invention.

A detailed description of the technical solutions of the present invention is provided below, along with the accompanying drawings. It should be understood that the specific embodiments described herein are for illustrative purposes only and do not limit the scope of the invention. The scope of the present invention is not limited by these embodiments, but is determined by the scope of the patent application.

The preparation method used in the present invention, as exemplified by Comparative Examples 1-3 and Examples 1-5, involves 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 before tableting. The compression pressure in this manufacturing method can be appropriately adjusted according to the formulation and tablet shape, and is preferably in the range of 4 to 14 kN.

The dissolution test used in this invention evaluates the dissolution results of pharmaceutical compositions or tablets prepared, for example, in low-dose examples and comparative examples. Specifically, tablets containing the pharmaceutical composition are subjected to a dissolution test using a dissolution test apparatus under the following conditions: 37°C, 900 mL of water, and a paddle speed of 50 rpm. Subsequently, the sample solution is analyzed using HPLC under the following conditions: a mobile phase consisting of a mixture of an 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.

The stability test used in this invention evaluates the impurity results of pharmaceutical compositions or tablets prepared, for example, in high-dose examples and comparative examples. Specifically, tablets containing the pharmaceutical composition are subjected to a stability test under the following conditions: 40°C/75% RH. Next, 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 is used, with a C18 column having 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.

Other components used in this invention include excipients, binders, lubricants, disintegrants, surfactants, plasticizers, colorants, and other pharmaceutically acceptable components.

The excipients used in this invention include, for example, crystalline cellulose or lactose (e.g., lactose monohydrate), D-mannitol, sucrose, corn starch, calcium phosphate, sorbitol, light anhydrous silicic acid, etc., with crystalline cellulose and lactose being preferred.

The binders used in this invention include, for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose (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 to 140,000 mPa·s, such as hypromellose 2208 (Methocel® K4M Premium CR), has a viscosity of 2,500 to 5,000 mPa·s.

The lubricants used in this 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.

The disintegrants used in this invention include, for example, crospovidone, low-substituted hydroxypropylcellulose, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose, carboxymethylcellulose calcium, and potato starch, with crospovidone being preferred.

Table 1 shows the tablet formulations for Comparative Example 1, Comparative Example 2, and Comparative Example 3.

The preparation method is as follows:
1. Ingredients: Weigh guanfacine hydrochloride (active ingredient), fumaric acid (organic acid), and Eudragit L100-55 (enteric coating agent) according to the formula.
Other components: for example, 13% to 50% binders, no more than 5% disintegrants, and 10% to 70% excipients.
Each of the above components is sieved using a 40-mesh sieve.

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

3. Tablet compression:
The tablets are compressed according to the weight determined in the interim test. A circular 7.0 mm punch is used for compression, with a hardness of 4N to 14N and a weight difference of ±5%.

Table 2 shows the tablet formulations for Examples 1, 2, and 3.

The preparation method is as follows:
1. Weigh the ingredients: guanfacine hydrochloride, sodium bisulfite (inorganic acid), and Eudragit L100-55 (enteric coating agent) according to the formula.
Other components: for example, 13% to 50% binders, no more than 5% disintegrants, and 10% to 70% excipients.
Each of the above components is sieved using a 40-mesh sieve.

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

3. Tablet compression:
The tablets are compressed according to the weight determined in the interim test. A circular 7.0 mm punch is used for compression, with a hardness of 4N to 14N and a weight difference of ±5%.

The tablet formulations for Examples 4 and 5 are shown in Table 3.

The preparation method is as follows:
1. Weigh the ingredients: guanfacine hydrochloride, boric acid (inorganic acid), and Eudragit L100-55 (enteric coating agent) according to the formula.
Other components: for example, 13% to 50% binders, no more than 5% disintegrants, and 10% to 70% excipients.
Each of the above components is sieved using a 40-mesh sieve.

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

3. Tablet compression:
The tablets are compressed according to the weight determined in the interim test. A circular 7.0 mm punch is used for compression, with a hardness of 4N to 14N and a weight difference of ±5%.

4. Dissolution test using HPLC Analytical 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 aqueous solution and acetonitrile (adjusted to pH 10 with sodium hydroxide).
(3) Injection volume: 20 μL.
(4) Flow rate: 1.2 mL/min.
(5) Temperature: 27℃
(6) Detection wavelength: UV 220 nm.

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 (pH adjusted to 10 with sodium hydroxide).
(3) Injection volume: 100 μL.
(4) Flow rate: 1 mL/min.
(5) Temperature: 27℃
(6) Detection wavelength: UV 220 nm.

The dissolution test method conformed to pharmacopoeia standards, using 900 mL of water at 37°C as the solvent, with a rotation speed of 50 rpm. Sampling for analysis was performed at 4, 8, 12, and 24 hours.

The dissolution curves of the tablets in the examples and comparative examples in the dissolution test are described below. Please refer to Figures 1 to 3.

The dissolution profiles of tablets 1, 2, and 3 under 37°C conditions were examined. The experimental results are shown in Figure 1 and Table 4.

From the dissolution test data shown in Figure 1, it was confirmed that in the comparative example of the present invention, tablets prepared using fumaric acid as an organic acid additive showed release of the active ingredient in water for more than 24 hours, confirming the stability of the pharmaceutical composition over time. According to the experimental results, when a low dose of fumaric acid, 1 mg, was added, 35.17% was released in 4 hours, reaching 44.43% in 12 hours, and it was clear that it stabilized in 24 hours. When a medium dose of fumaric acid, 3 mg, was added, 36.40% was released in 4 hours, reaching 51.33% in 8 hours, and 57.07% in 24 hours. When a high dose of fumaric acid, 7.5 mg, was added, 45.05% was released in 4 hours, reaching 65.45% in 8 hours, 73.95% in 12 hours, and 80.95% in 24 hours. These experimental results clearly show that increasing the organic acid concentration increases the release of tablets in water, and even a slight increase in organic acid concentration significantly affects the release rate of tablets, especially when taken with water. Therefore, tablets containing organic acids tend to exhibit unstable drug release during prescription, affecting bioavailability and other factors.

The dissolution test curves of the tablets from Examples 1, 2, and 3 under 37°C conditions are examined. The experimental results are shown in Figure 2 and Table 5.

From the dissolution test data shown in Figure 2, it was confirmed that in the comparative example of the present invention, tablets prepared using sodium bisulfite as an inorganic acid additive showed release of the active ingredient in water for more than 24 hours, confirming the stability of the pharmaceutical composition's mass over time. According to the experimental results, when a low dose of 7.5 mg of sodium bisulfite, an inorganic acid, was added, 22.80% was released in 4 hours, reaching 31.65% in 12 hours and 39.60% in 24 hours. When a medium dose of 20 mg of sodium bisulfite, an inorganic acid, was added, 19.40% was released in 4 hours, reaching 25.65% in 8 hours and 39.10% in 24 hours. When a high dose of 40 mg of sodium bisulfite, an inorganic acid, was added, 19.45% was released in 4 hours, reaching 27.15% in 8 hours, 32.00% in 12 hours and 51.30% in 24 hours. These experimental results show that, compared to the comparative example, the examples with different proportions of the inorganic acid sodium bisulfite achieved a well-stable release rate. Therefore, this formulation design can improve the stability of the tablet manufacturing process, reduce variability in tablet release within the body during patient ingestion, and achieve advantages over organic acid formulations both during manufacturing and in vivo.

The dissolution test curves of the tablets from Examples 4 and 5 under 37°C conditions are examined. The experimental results are shown in Figure 3 and Table 6.

From the dissolution test data in Figure 3, it was confirmed that the tablets prepared in the present invention with boric acid as an inorganic acid additive showed release of the active ingredient in water for more than 24 hours, and that the mass of the pharmaceutical composition was maintained stably over time. According to the experimental results, when a low dose of 3.75 mg of boric acid was added, 23.05% was released after 4 hours, 26.70% after 8 hours, 28.10% after 12 hours, and 28.80% after 24 hours. Similarly, when a high dose of 7.5 mg of boric acid was added, 26.70% was released after 4 hours, 30.30% after 8 hours, 31.30% after 12 hours, and 32.85% after 24 hours. These experimental results show that, compared to the comparative example, Examples 4 and 5 achieved 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, reduce variability in the release of tablets into the body during patient administration, and offer advantages over organic acid formulations both during manufacturing and in vivo.

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

The USP Pharmacopoeia testing specifications state that the impurity of 2,6-dichlorophenylacetic acid should be less than 1.0%, peak 1 (unidentifiable degradation product) less than 0.5%, and all impurities (total impurities) less than 1.5%. This is used to evaluate impurities and degradation products that occur during storage. The tablets prepared in the comparative example initially contained 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. The experimental results showed that the tablets prepared in the comparative example containing organic acid additives were destroyed and unstable under high temperature and high humidity conditions. The tablets prepared in the example initially contained 0.1% 2,6-dichlorophenylacetic acid, with no peak 1 detected, and all impurities present at 0.1%. Experimental results showed that the tablets prepared in the example containing the inorganic acid additive were more stable than the comparative example tablets under high temperature and humidity conditions, demonstrating stable quality of the pharmaceutical composition regardless of changes in time, temperature, and humidity.

(Note)
(Note 1)
A pharmaceutical composition comprising guanfacine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable inorganic acid.

(Note 2)
The pharmaceutical composition described in Appendix 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.

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

(Note 4)
The pharmaceutical composition according to Appendix 1, wherein the content of the inorganic acid is 2.5% to 27% by weight of the pharmaceutical composition.

(Note 5)
The pharmaceutical composition according to Appendix 1, 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.

(Note 6)
The pharmaceutical composition according to Appendix 1, comprising an excipient, wherein the excipient is selected from the group consisting of crystalline cellulose, lactose, D-mannitol, sucrose, corn starch, calcium phosphate, sorbitol, and light anhydrous silicic acid.

(Note 7)
The pharmaceutical composition as described in Appendix 1, comprising a binder, wherein the binder is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, N-vinylpyrrolidone, vinyl acetate, pregelatinized starch, gelatin, agar, and gum arabic.

(Note 8)
The pharmaceutical composition as described in Appendix 1, comprising a lubricant, wherein the lubricant is selected from the group consisting of 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 ester.

(Note 9)
A pharmaceutical composition as described in Appendix 1, in the form of a tablet.

(Note 10)
A method for producing the pharmaceutical composition described in Appendix 1, characterized by comprising guanfacine or a pharmaceutically acceptable salt thereof, prepared by mixing, optionally granulating, final mixing, and compressing into tablets, and a pharmaceutically acceptable inorganic acid.

Claims (10)

A pharmaceutical composition comprising guanfacine or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable inorganic acid, and a lubricant, wherein the inorganic acid is selected from the group consisting of sodium bisulfite and boric acid, and the lubricant is selected from the group consisting of 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. The pharmaceutical composition according to claim 1, wherein the content of the inorganic acid is 30% by weight or less of the pharmaceutical composition. The pharmaceutical composition according to claim 1, wherein the content of the inorganic acid is 2.5% to 27% by weight of the pharmaceutical composition. The pharmaceutical composition according to claim 1, 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. The pharmaceutical composition according to claim 1, comprising an excipient, wherein the excipient is selected from the group consisting of crystalline cellulose, lactose, D-mannitol, sucrose, corn starch, calcium phosphate, sorbitol, and light anhydrous silicic acid. The pharmaceutical composition according to claim 1, comprising a binder, wherein the binder is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, N-vinylpyrrolidone, vinyl acetate, pregelatinized starch, gelatin, agar, and gum arabic. The pharmaceutical composition according to claim 1, in the form of a tablet. A method for producing the pharmaceutical composition according to claim 1, characterized by comprising guanfacine or a pharmaceutically acceptable salt thereof, prepared by mixing, granulating, final mixing, and tablet compression, and a pharmaceutically acceptable inorganic acid. A method for producing the pharmaceutical composition according to claim 1, characterized by comprising guanfacine or a pharmaceutically acceptable salt thereof, prepared by mixing, final mixing, and tablet compression, and a pharmaceutically acceptable inorganic acid. A method for producing a pharmaceutical composition, which is prepared by mixing, granulating, final mixing, and compressing tablets,
The aforementioned pharmaceutical composition,
The product comprises guanfacine or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable inorganic acid, and a lubricant, wherein the inorganic acid is selected from the group consisting of phosphoric acid, sodium bisulfite, and boric acid, and the lubricant is selected from the group consisting of 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.
Manufacturing method.