A Guanfacinol Hydrochloride Extended-Release Tablet and Its Preparation Method

Abstract

This invention discloses a guanifacine hydrochloride sustained-release tablet and its preparation method. The method includes placing a granulated / mixed, tableted guanifacine hydrochloride pharmaceutical composition into a hot air device for drying. The hot air device is selected from a coating machine or an oven, and the hot air temperature ranges from 30 to 70°C. After drying, the resulting guanifacine hydrochloride sustained-release tablet has a moisture content ≤4.0% by weight, preferably ≤3.5% by weight. The guanifacine hydrochloride pharmaceutical composition contains guanifacine hydrochloride, lactose, microcrystalline cellulose, hydroxypropyl methylcellulose, methacrylate copolymer, fumaric acid, glyceryl behenate, sodium stearate fumarate, and micronized silica gel. This hot air drying process effectively controls the total impurities of the guanifacine hydrochloride sustained-release tablets to ≤1.0% and the single impurities to ≤0.1%. This process improves the safety and stability of the drug, is easy to operate, and is suitable for commercial production.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a guanifacine hydrochloride sustained-release tablet and its preparation method. Background Technology

[0002] Guanifacin hydrochloride is the first selective α-2A adrenergic receptor agonist approved globally for the treatment of this indication, exhibiting a 15-20 fold higher affinity for this receptor subtype compared to α-2B or α-2C subtypes. The mechanism of action of guanifacin hydrochloride in the treatment of ADHD is not fully understood. Preclinical studies have shown that guanifacin hydrochloride regulates signaling in the prefrontal cortex and basal ganglia through direct modification of synaptic norepinephrine transmission in α-2 adrenergic receptors. The chemical name of guanifacin hydrochloride is N-amidinyl-2-(2,6-dichlorophenyl)acetamide monohydrochloride, with the molecular formula C9H9Cl2N3O·HCl, a molecular weight of 282.55, and a structural formula of:

[0003]

[0004] Guanfaxine hydrochloride is a white to off-white crystalline powder that is sparingly soluble in water and ethanol, but has relatively high solubility in methanol.

[0005] On September 2, 2009, the U.S. FDA approved guanifacine hydrochloride extended-release tablets (brand name). It is used to treat attention deficit hyperactivity disorder (ADHD) in children and adolescents aged 6 to 17. It is a once-daily oral formulation, available in four dosage strengths: 1, 2, 3, and 4 mg / tablet. The EMEA also approved this once-daily non-stimulant medication on September 17, 2015. Guanfaxine hydrochloride extended-release tablets are used to treat attention deficit hyperactivity disorder (ADHD) and are indicated for children and adolescents aged 6-17 years who are unsuitable for, intolerant of or have shown no response to stimulants. The approval of guanfaxine hydrochloride extended-release tablets in the treatment of ADHD in children and adolescents in Europe marks a significant advance.

[0006] Currently, Chinese patent CN102579381 discloses a guanifacine hydrochloride sustained-release formulation and its preparation method, using a wet granulation process. Specifically, this method exposes the active ingredient directly to water, overheating, or high shear stress. Experimental studies have shown that this preparation process makes it difficult to control related substances in the drug composition, resulting in poor product stability. Furthermore, the total impurities in the guanifacine hydrochloride do not meet pharmaceutical standards. US patents US6811794 and CN103705480 disclose solid oral dosage forms of guanifacine drug compositions, with tablets prepared using a direct compression method. This preparation process also struggles to effectively control the moisture content of the drug composition, leading to poor impurity stability and raising concerns about the safety of this solid oral dosage form. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a guanifacine hydrochloride sustained-release tablet and a method for preparing the same, specifically a method for preparing guanifacine hydrochloride sustained-release tablet and a method for improving the stability of guanifacine hydrochloride sustained-release tablet.

[0008] This invention effectively controls related substances in guanifacine hydrochloride sustained-release tablets under accelerated and forced acceleration conditions. The technical solution of this invention reduces the moisture content of guanifacine hydrochloride sustained-release tablets, effectively reducing the instability of impurities in the pharmaceutical composition and ensuring the stability of the pharmaceutical composition for use. Furthermore, the preparation method is simple and suitable for large-scale production.

[0009] This invention provides a method for preparing guanifacine hydrochloride sustained-release tablets. The method includes placing a granulated / mixed, tableted guanifacine hydrochloride pharmaceutical composition into a hot air device for drying. The hot air device is selected from a coating machine or an oven, and the hot air temperature ranges from 30 to 70°C. After drying, the guanifacine hydrochloride sustained-release tablets have a moisture content of ≤4.0% by weight, preferably ≤3.5% by weight.

[0010] The present invention also provides that when the hot air device is selected from the coating machine, the specific steps include placing the granulated / mixed and tableted guanifacine hydrochloride drug composition in the coating pan, controlling the air inlet temperature and air inlet volume of the coating pan, adjusting the drum speed of the coating pan, and drying for 2 to 8 hours to obtain stable guanifacine hydrochloride sustained-release tablets.

[0011] The present invention provides a preferred coating pan with a drum rotation speed of 2 to 10 rpm;

[0012] The present invention provides that the air inlet temperature of the coating pan is 30-70°C, preferably 35-65°C, and more preferably 40-60°C;

[0013] The present invention provides a coating pan with an air inlet volume of 500-2000 m³ / h. 3 / h, preferably 700~1500m 3 / h;

[0014] The present invention provides a coating pan drying time of 2 to 8 hours.

[0015] When the hot air device provided by this invention is selected from an oven, the specific steps include placing the granulated / mixed and tableted guanifacine hydrochloride drug composition in an oven, controlling the oven temperature, and drying for 4-12 hours to obtain stable guanifacine hydrochloride sustained-release tablets.

[0016] The present invention provides an oven temperature of 30-70℃, preferably 40-60℃.

[0017] After drying using a hot air device selected from a coating machine or an oven, the present invention also provides a guanidine hydrochloride sustained-release tablet with a moisture content ≤4.0% by weight, preferably ≤3.5% by weight after drying. The total impurity limit is ≤1.0%, and the single impurity limit is ≤0.10%. Preferably, the total impurity limit is ≤0.5%, and the single impurity limit is ≤0.08%. More preferably, the total impurity limit is ≤0.3%, and the single impurity limit is ≤0.05%.

[0018] The present invention also provides a guanifacine hydrochloride pharmaceutical composition comprising guanifacine hydrochloride, lactose, microcrystalline cellulose, hydroxypropyl methylcellulose, methacrylate copolymer, fumaric acid, behenicol glyceride, sodium stearate fumarate, and micronized silica.

[0019] This invention also provides a guanifacine hydrochloride pharmaceutical composition in strengths of 1, 2, 3, and 4 mg, wherein the pharmaceutical composition is prepared by wet granulation or direct compression, and the formulation of the pharmaceutical composition contains:

[0020]

[0021]

[0022] The present invention also provides a preferred guanifacine hydrochloride pharmaceutical composition, wherein the pharmaceutical composition comprises 1, 2, 3 and 4 mg strengths as follows:

[0023]

[0024] This invention provides a method for improving the impurity stability of guanifacine hydrochloride sustained-release tablets. The total impurity limit of the guanifacine hydrochloride sustained-release tablets prepared by this method is ≤1.0%, and the limit for a single impurity is ≤0.10%. Preferably, the total impurity limit is ≤0.5%, and the limit for a single impurity is ≤0.08%. More preferably, the total impurity limit is ≤0.3%, and the limit for a single impurity is ≤0.05%. This significantly reduces the impurity content of pharmaceutical compositions in the prior art. This invention can obtain high-purity, high-quality guanifacine hydrochloride sustained-release tablets.

[0025] More specifically, after being placed under forced accelerated conditions (temperature 60±2℃, relative humidity 75%±5%) for 10 days, the total impurity content of the drug composition remained essentially unchanged, with some changes also within 0.10%. Furthermore, after being examined under accelerated conditions (temperature 40±2℃, relative humidity 75%±5%, the same accelerated conditions specified in the Guidelines for Stability Testing of Raw Materials and Preparations in Chapter 9001 of the 2015 edition of the Chinese Pharmacopoeia) for 6 months, the total impurity content remained essentially unchanged, with some changes also within 0.10%. The product exhibits good stability and is easier to store.

[0026] This invention also provides a guanifacine hydrochloride pharmaceutical composition, the excipients of which are lactose, microcrystalline cellulose, hydroxypropyl methylcellulose, methacrylate copolymer, fumaric acid, glyceryl behenate, sodium stearate fumarate, and micronized silica gel. Preferably, the above formulation has the same in vitro release rate as the reference formulation (see appendix). Figure 1-3 The release test conditions were as follows: dissolution test apparatus, rotation speed 75 rpm, temperature 37℃, release medium 900 ml, hydrochloric acid buffer solution with pH 2.2, and detection method was high performance liquid chromatography.

[0027] In summary, this invention provides a novel process for drying guanifacine hydrochloride sustained-release tablets using a hot air device, either a coating machine or an oven. Hot air drying reduces the moisture content of the composition, thereby optimizing the total impurity content and drug stability, while ensuring controllable drug release. This invention effectively reduces the related substance risk of guanifacine hydrochloride sustained-release tablets, improves drug safety, produces a stable drug composition, and features a simple preparation process suitable for commercial production. Attached Figure Description

[0028] Figure 1 The in vitro release curve of the sample obtained in Example 3 of this invention under pH 2.2 conditions;

[0029] Figure 2 The in vitro release curve of the sample obtained in Example 5 of this invention under pH 2.2 conditions;

[0030] Figure 3 The in vitro release curve of the sample obtained in Example 6 of this invention under pH 2.2 conditions;

[0031] Figure 4 The in vitro release curve of the sample obtained in Example 8 of this invention under pH 2.2 conditions. Detailed Implementation

[0032] The present invention will be further described in detail below with reference to the embodiments, but the implementation methods and protection scope of the present invention are not limited thereto.

[0033] Comparative Example 1: The drug composition was mixed according to the formulation in the table below and tableted to obtain guanifacine hydrochloride sustained-release tablets.

[0034] Table 1. Prescription for Guanfaxine Hydrochloride Extended-Release Tablets 2mg

[0035]

[0036] Comparative Example 2: The raw material composition of Guanfaxine Hydrochloride Extended-Release Tablets is shown in Table 2 below. Various raw materials and excipients were prepared according to the composition of Guanfaxine Hydrochloride Extended-Release Tablets as described in the table. The prepared Guanfaxine Hydrochloride, lactose, fumaric acid, hydroxypropyl methylcellulose, and methacrylic acid copolymer were passed through an 80-mesh sieve and mixed in a high-speed mixer for 30 minutes to obtain a uniform powder. Then, 144g of purified water (a binder) was slowly added under high-speed shearing conditions using a high-speed shearing machine. The granules obtained from high-shear granulation were dried in a fluidized bed until the moisture content (LOD) of the dry granules was ≤5%. The dry granules were then sieved through a 16-mesh sieve. After sizing, 3.6g of prepared glidant (micronized silica gel) and 3.6g of lubricant (magnesium stearate) were added, and the mixture was stirred until uniform. Finally, the mixture was compressed and packaged to obtain the finished Guanfaxine Hydrochloride Extended-Release Tablets.

[0037] Table 2. Prescription for Guanfaxine Hydrochloride Extended-Release Tablets 2mg

[0038]

[0039] Comparative Example 3: The raw and excipient composition of Guanfaxine Hydrochloride Extended-Release Tablets is shown in Table 3 below. Various raw and excipients were prepared according to the raw and excipient composition of Guanfaxine Hydrochloride Extended-Release Tablets as shown in the table below. First, Guanfaxine Hydrochloride, pregelatinized starch, citric acid, sodium hydroxypropyl cellulose, and hydroxyethyl cellulose were passed through an 80-mesh sieve. Then, Guanfaxine Hydrochloride, pregelatinized starch, citric acid, sodium hydroxypropyl cellulose, and hydroxyethyl cellulose were put into a mixer and mixed evenly. Next, lubricant and disintegrant were added to the mixer in sequence and mixed evenly to obtain a mixed powder. Finally, the powder was compressed and packaged to obtain the finished Guanfaxine Hydrochloride Extended-Release Tablets.

[0040] Table 3. Prescription for Guanfaxine Hydrochloride Extended-Release Tablets 1mg

[0041]

[0042]

[0043] Example 1: Using the present invention, tablets prepared in Comparative Example 2 were placed in a high-efficiency coating pan with a batch size of 1 kg tablets. The tablet bed temperature was adjusted to 40°C, the coating pan speed to 6 rpm, and the air intake to 1000 m³ / h. 3 After drying for 5 hours, samples were taken and packaged to obtain the finished product, guanifacine hydrochloride sustained-release tablets.

[0044] Example 2: Using the present invention, tablets prepared in Comparative Example 3 were placed in a high-efficiency coating pan with a batch size of 1 kg tablets. The tablet bed temperature was adjusted to 40°C, the coating pan speed to 6 rpm, and the air intake to 1000 m³ / h. 3 After drying for 6 hours, samples were taken and packaged to obtain the finished product, guanifacine hydrochloride sustained-release tablets.

[0045] Example 3: Using the present invention, tablets prepared in Comparative Example 1 were placed in a high-efficiency coating pan with a batch size of 1 kg tablets. The tablet bed temperature was adjusted to 30°C, the coating pan speed to 6 rpm, and the air intake to 1200 m³ / h. 3 After drying for 6 hours, samples were taken and packaged to obtain stable guanifacine hydrochloride extended-release tablets. The obtained stable guanifacine hydrochloride extended-release tablets showed consistent in vitro release curves with the reference formulation (see...). Figure 1 ).

[0046] Example 4: Using the present invention, tablets prepared in Comparative Example 1 were placed in a high-efficiency coating pan with a batch size of 1 kg tablets. The tablet bed temperature was adjusted to 60°C, the coating pan speed to 3 rpm, and the air intake to 1000 m³ / h. 3 After drying for 5 hours, samples were taken and packaged to obtain stable guanifacine hydrochloride sustained-release tablets.

[0047] Example 5: Using the present invention, tablets prepared in Comparative Example 1 were placed in a high-efficiency coating pan with a batch size of 1 kg tablets. The tablet bed temperature was adjusted to 70°C, the coating pan speed to 9 rpm, and the air intake to 600 m³ / h. 3 After drying for 2 hours, samples were taken and packaged to obtain stable guanifacine hydrochloride extended-release tablets. The obtained stable guanifacine hydrochloride extended-release tablets showed consistent in vitro release curves with the reference formulation (see...). Figure 2 ).

[0048] Example 6: Using the present invention, the tablets prepared in Comparative Example 1 were placed in an oven and dried at 30°C for 12 hours before packaging to obtain stable guanifacine hydrochloride extended-release tablets. The obtained stable guanifacine hydrochloride extended-release tablets showed consistent in vitro release curves with the reference formulation (see...). Figure 3 ).

[0049] Example 7: Using the present invention, the tablets prepared in Comparative Example 1 were placed in an oven and dried at 60°C for 7 hours before being packaged to obtain stable guanifacine hydrochloride sustained-release tablets.

[0050] Example 8: Using the present invention, the tablets prepared in Comparative Example 1 were placed in an oven and dried at 70°C for 4 hours before packaging to obtain stable guanifacine hydrochloride extended-release tablets. The obtained stable guanifacine hydrochloride extended-release tablets showed consistent in vitro release curves with the reference formulation (see...). Figure 4 ).

[0051] Note: Comparative Examples 1 and 3-8 all used the same batch of guanifacine hydrochloride extended-release tablets. Comparative Example 2 used the same batch of guanifacine hydrochloride extended-release tablets as Example 1. Comparative Example 3 used the same batch of guanifacine hydrochloride extended-release tablets as Example 2.

[0052] Example 9: Stability Test

[0053] The finished products obtained from Comparative Examples 1-3 and 1-8 were placed in a constant temperature and humidity chamber under forced acceleration conditions for 10 days or 6 months, and the impurity percentage (%) of the drug composition was determined by the area normalization method. The moisture content (%) of the drug composition was determined by the Fischer method as described in the Chinese Pharmacopoeia. The results are as follows:

[0054] Table 4

[0055]

[0056] Table 5

[0057]

[0058]

[0059] The results show that after 10 days of accelerated testing, the total impurity limit of the guanifacine hydrochloride sustained-release tablets in Examples 3, 4, 5, 6, 7, and 8 after drying was ≤1.0%, the maximum single impurity limit was ≤0.1%, and the moisture content was controlled at ≤4.0%. After 6 months of accelerated testing, the total impurity limit of the guanifacine hydrochloride sustained-release tablets in Examples 3, 4, 5, 6, 7, and 8 after drying was ≤1.0%, the maximum single impurity limit was ≤0.1%, and the moisture content was controlled at ≤4.0%. The total impurity content of the examples showed little change after storage. For the undried formulation, the impurity content reached 1.61% after 10 days of accelerated testing, indicating a rapid increase in impurities. The moisture content of the guanifacine hydrochloride sustained-release tablets prepared using the wet granulation process was controlled at 5.1%, indicating a relatively large increase in impurities. The present invention, by drying the pharmaceutical composition prepared using this process, can reduce the rate of impurity increase. Therefore, the guanifacine hydrochloride sustained-release tablets of the present invention, by effectively controlling the impurity limits, exhibit high formulation stability and better meet the requirements of relevant clinical drug regulations.

Claims

1. A method for preparing guanifacine hydrochloride sustained-release tablets, the method comprising placing the compressed guanifacine hydrochloride pharmaceutical composition into a hot air device for drying, wherein the hot air device is selected from a coating machine or an oven, and the dried tablets have a moisture content ≤4.0% by weight, wherein the guanifacine hydrochloride pharmaceutical composition contains: The total impurity limit for Guanfacin hydrochloride sustained-release tablets is ≤1.0%, and the limit for a single impurity is ≤0.1%.

2. The method according to claim 1, characterized in that, The dried guanethidine hydrochloride sustained-release tablets have a moisture content of ≤3.5% by weight.

3. The method according to claim 1 or 2, characterized in that, When the hot air device is selected from the coating machine, the specific steps include placing the tableted guanifacine hydrochloride drug composition into the coating pan, controlling the air inlet temperature and air volume of the coating pan, adjusting the drum speed of the coating pan, and performing drying treatment to obtain guanifacine hydrochloride sustained-release tablets.

4. The method according to claim 3, characterized in that, The drum rotation speed of the coating pan is 2-10 rpm; the air inlet temperature of the coating pan is 30-70℃; and the drying time required for the drying process is 2-8 hours.

5. The method according to claim 3, characterized in that, The air intake volume of the coating pan is 500-2000 m³ / h. 3 / h.

6. The method according to claim 1, characterized in that, When the hot air device is selected from an oven, the specific steps include placing the tableted guanifacine hydrochloride drug composition in the oven, controlling the oven temperature, and performing drying treatment to obtain guanifacine hydrochloride sustained-release tablets.

7. The method according to claim 6, characterized in that, The oven temperature is 30-70℃; the drying time required for the drying process is 4-12 hours.

8. The method according to claim 4, characterized in that, The air inlet temperature of the coating pan is 35-65℃.

9. The method according to claim 4, characterized in that, The air inlet temperature of the coating pan is 40-60℃.

10. The method according to claim 5, characterized in that, The air intake volume of the coating pan is 700-1500 m³ / h. 3 / h.

11. The method according to claim 7, characterized in that, The oven temperature is 40-60℃.

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