Guanfacine hydrochloride multifunctional drug release composition and preparation method thereof

Abstract

The invention relates to a multifunctional medicine release composition as well as a preparation method and application thereof. The multifunctional medicine release composition has a treatment effect on attention deficit and attention disorder of children. The invention also provides a dispersible sustained-release multi-unit pellet system which comprises an active pharmaceutical ingredient and pharmaceutically acceptable auxiliary materials, and the active pharmaceutical ingredient exists in the core pellet. The invention also relates to a method for preparing the sustained-release multi-unit pellet system by adopting a multi-seal coating technology. The dispersible slow-release multi-unit pellet system disclosed by the invention has a good release characteristic.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, and more specifically, to medications for Attention Deficit Hyperactivity Disorder (ADHD) in children and adolescents. The invention also relates to formulations, uses, and methods of preparation of said medications. Background Technology

[0002] In 2009, the U.S. FDA approved Shire's guanifacine hydrochloride extended-release tablet, Intuniv, for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents aged 6-17 years, as a monotherapy and adjunctive therapy to stimulant medications. Intuniv is a centrally acting drug. Guanifacin hydrochloride is a 2A adrenergic receptor agonist, taken orally once daily. Its solubility varies significantly with different pH levels. Guanifacin hydrochloride has good solubility in acidic solutions, but solubility decreases as pH increases. Therefore, Shire has developed a sustained-release formulation utilizing both a sustained-release material and a pH-sensitive material to accelerate drug release at high pH environments.

[0003] The sustained-release formulation developed by Shire contains a pH-sensitive material in its core composition, which affects drug release due to variations in the pH level of the patient's intestines. This sustained-release formulation is susceptible to gastrointestinal peristalsis and compression, posing a risk of sudden drug release.

[0004] In order to overcome the above-mentioned problems in the prior art, this application provides a novel multifunctional drug release composition for guanifacine hydrochloride, which effectively improves the dissolution and release characteristics of guanifacine hydrochloride. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and provide a drug that has a good therapeutic effect on attention deficit hyperactivity disorder in children and adolescents.

[0006] The invention is described in more detail below to aid in understanding it.

[0007] It should be understood that the terms or words used in the specification and claims should not be construed as having the meaning defined in a dictionary, but rather as having a meaning consistent with their meaning in the context of the invention, based on the principle that the concept of a term may be appropriately defined by the inventor for the best explanation of the invention.

[0008] As described herein, the term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions known in the art. Representative pharmaceutically acceptable salts include, but are not limited to: hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, phosphate, acetate, butyrate, adipate, heptanate, hexanoate, maleate, fumarate, citrate, benzoate, benzenesulfonate, aspartate, camphorate, camphorsulfonate, disglucuronide, cyclopentanepropionate, ethanesulfonate, lactate, methanesulfonate, nicotinate, oxalate, picrate, neopentanoate, propionate, succinate, tartrate, thiocyanate, and p-toluenesulfonate.

[0009] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms or pellets, the active compound is combined with at least one conventional inert excipient, carrier, or formulation. It includes: (a) fillers, such as starch, glucose, lactose, sucrose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginic acid, certain complex silicates, and sodium carbonate; (d) wetting agents, such as cetyl alcohol and glyceryl monostearate; and (e) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof; (f) plasticizers: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, triethyl citrate, tributyl citrate, acetylated citrate, polyethylene glycol; and (g) controlled-release materials: acrylic resins, such as Eudragit RS100, Eudragit L100-55, Eudragit RL100, Eudragit NE30D / NM30D, Eudragit RSPO. Capsules, tablets, and pills may also contain buffers, such as organic acids like citric acid, tartaric acid, and lactic acid; inorganic acids like phosphoric acid and hydrochloric acid; alkali hydroxides like sodium hydroxide and calcium hydroxide; and amines like triethanolamine, diethanolamine, and diisopropanolamine. Additionally, deodorants, dispersants, preservatives, and fragrances may be used as needed.

[0010] The compounds of the present invention shall be administered in a therapeutically effective amount using any of the recognized methods of administration of agents with similar effects. The compounds of the present invention may be administered as a single daily dose, or the total daily dose may be divided into two, three, or four daily doses.

[0011] It should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, time of administration, route of administration, elimination rate, drug combination, and the severity of the specific disease being treated. The therapeutically effective dose for a given situation can be readily determined through routine laboratory testing and is within the skill and judgment of an average clinician.

[0012] The present invention provides an oral pharmaceutical composition comprising at least two microspheres: (i) microspheres of guanifacin or a pharmaceutically acceptable salt thereof released at a first rate; and (ii) microspheres of guanifacin or a pharmaceutically acceptable salt thereof released at a second rate and a pharmaceutically acceptable excipient.

[0013] Furthermore, the first rate of release is faster than the second rate of release.

[0014] Furthermore, the guanifacine released at the first rate accounts for 10% to 50% of the total weight of guanifacine; the guanifacine released at the second rate accounts for 50% to 90% of the total weight of guanifacine.

[0015] Furthermore, the second rate of release is a slow-release process.

[0016] Furthermore, the oral pharmaceutical composition is a capsule.

[0017] Furthermore, (i) and (ii) also contain at least one excipient.

[0018] Furthermore, the excipient is selected from slow-release agents, lubricants, plasticizers, adhesives, and fillers.

[0019] Further, at least one of the excipients in (i) and (ii) is a slow-release agent. Preferably, the slow-release agent is selected from acrylic polymers such as Eudragit RS100, Eudragit L100-55, Eudragit RL100, Eudragit NE30D / NM30D, Eudragit RSPO, or a mixture of one or more. Preferably, the slow-release polymer is selected from Eudragit RS100, Eudragit L100-55, or a combination thereof.

[0020] Further, at least one of the excipients in (i) and (ii) is an adhesive, preferably selected from hydroxypropyl cellulose and hydroxypropyl methylcellulose.

[0021] Further, at least one of the excipients in (i) and (ii) is a plasticizer, preferably selected from triethyl citrate, tributyl citrate, acetylsulphate, polyethylene glycol, or mixtures thereof.

[0022] Furthermore, the outermost layer of the microcapsules (i) and (ii) is a sustained-release layer containing a sustained-release agent, wherein the weight gain of the sustained-release layer coating in the microcapsules is 8%-9.5% WG, and the weight gain of the sustained-release layer coating in the microcapsules is 14.5%-15.5% WG.

[0023] This invention relates to a multifunctional drug release composition and its preparation method. Specifically, this invention relates to a first group of pharmaceutically active substances comprising a pharmaceutically active substance released at a first rate and a second group of pharmaceutically active substances comprising a pharmaceutically active substance released at a second rate.

[0024] Furthermore, this invention relates to a novel dispersible sustained-release multi-unit microsphere system comprising an active pharmaceutical ingredient and pharmaceutically acceptable excipients, wherein the active pharmaceutical ingredient is present in a core microsphere. More specifically, this invention relates to a novel method for preparing a sustained-release multi-unit microsphere system using a multiple sealing coating technique.

[0025] This invention utilizes a pH-sensitive material to alter the drug release rate of functional coating materials at high pH values.

[0026] When taken once daily, it can maintain an effective drug concentration in the body for 20 hours. At the same time, the drug release rate is not affected by the pH value of the intestines, and the drug release rate is not increased or deviated due to gastrointestinal peristalsis. It is safer, more effective and has fewer side effects than Shire's sustained-release formulation.

[0027] The multifunctional drug delivery composition is a final product composed of multi-unit microspheres that release drug at a first rate and multi-unit microspheres that release drug at a second rate. After administration, the composition subsequently disperses and smoothly delivers and releases the drug along the gastrointestinal tract to achieve the additive drug concentration of the first-rate drug release (faster release rate) and the second-rate drug release (slower release rate), thereby achieving a rapid peak drug concentration after administration and continuously prolonging the time for drug concentration to reach the target sustained-release time.

[0028] Sustained-release multi-unit microparticle systems can be effectively dispersed in the gastrointestinal tract, and drug release is controlled by coating. The microunits are usually spherical or near-spherical units with a diameter of less than 2 mm, containing active drugs.

[0029] In one embodiment, the present invention provides an orally administered multifunctional drug-release composition comprising a first group of pharmaceutically active substances released at a first rate and a second group of pharmaceutically active substances released at a second rate. The pharmaceutically active substances comprise guanfasine or a pharmaceutically acceptable salt thereof.

[0030] In one embodiment, the oral multifunctional drug delivery composition comprises: Core microparticles: composed of core materials with an average diameter of 50 μm to 1,200 μm; Drug coating layer: contains active pharmaceutical ingredients and optional excipients; The isolation coating layer covers the drug-containing microcapsules and is composed of a coating polymer. Functional coating layer: Microcapsules coated with an isolation coating layer, containing sustained-release agents and other excipients.

[0031] The active pharmaceutical ingredient is selected from guanfaxine or its pharmaceutically acceptable salt.

[0032] In one implementation, the pharmaceutically acceptable salt of guanfaxin is guanfaxin hydrochloride.

[0033] In another implementation, pharmaceutically acceptable excipients, carriers, or excipients may be used.

[0034] In yet another embodiment, the present invention provides the use of an orally administered multifunctional drug-release composition in the preparation of a medicament for treating attention deficit hyperactivity disorder in children and adolescents.

[0035] In yet another embodiment, the present invention also provides a method for preparing an orally administered multifunctional drug-release composition.

[0036] Compared with the prior art, the present invention has the following beneficial effects: This invention utilizes a functional polymer with low pH sensitivity and a functional polymer with high pH sensitivity to control the drug release rate through a thin film, achieving sustained release. Because it consists of multi-unit microspheres, the particles are uniformly distributed in the gastrointestinal tract, reducing the irritation of high-concentration drugs to the gastrointestinal mucosa. Another advantage is that even if the microsphere coating is incomplete, it will not lead to a burst release of the full dose, resulting in high safety. Due to the uniform particle size, it is unaffected by gastric emptying rate or food type, resulting in low fluctuations in blood drug concentration. The microspheres have good flowability and uniform size, facilitating coating, dosage dispensing, or tableting, and can also mask unpleasant tastes. Moreover, with the selection of specific sustained-release agent materials, the capsules of this invention can achieve sustained release even at high pH values ​​(pH=6.8) for up to 16 hours, achieving excellent technical results. Attached Figure Description

[0037] Figure 1 Dissolution characteristics of two types of microspheres and capsules in hydrochloric acid buffer at pH 2.2 in Examples 1-3.

[0038] Figure 2 Examples 4-6: Dissolution characteristics of two types of microspheres and capsules in hydrochloric acid buffer at pH 2.2.

[0039] Figure 3Dissolution characteristics of two capsule formulations in phosphate buffer at pH 6.8. Detailed Implementation

[0040] The preferred embodiments of the present invention are described below. It should be understood that the preferred embodiments described herein are for illustration and explanation only and are not intended to limit the present invention. Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in the art, or in accordance with the product instructions. Where the manufacturers of the reagents or instruments used are not specified, they are all conventional products that can be purchased through legitimate channels.

[0041] Example 1: Method for preparing a composition of a pharmaceutically active substance having a first release rate: Preparation of the drug coating solution: Guanifacin hydrochloride was added to hydroxypropyl cellulose dissolved in 95% ethanol / pure water to form a coating solution with a solid content of 3.5%.

[0042] Preparation of the isolation layer coating solution: Talc powder was dispersed in 95% ethanol / pure water and homogenized using a homogenizer. Then, it was added to a hydroxypropyl methylcellulose coating solution already dissolved in 95% ethanol, resulting in a solids content of 5.3%.

[0043] Preparation of the sustained-release coating solution: Talc powder was dispersed in 95% ethanol and homogenized using a homogenizer. Then, Eudragit RS100 and triethyl citrate coating solution, which had been dissolved in 95% ethanol, were added, resulting in a solid content of 8%.

[0044] The sucrose pellet cores were added to a fluidized bed and coated using a fluidized bed bottom spray coating process, sequentially applying the top layer coating solution, the isolation layer coating solution, and the sustained-release layer coating solution. After each layer of coating solution was sprayed, it was dried and sieved. The sustained-release layer coating had a weight gain of 9% WG (after drying, the pellets were passed through a 20-mesh sieve and a 60-mesh sieve, and the pellets between the 20-mesh and 60-mesh sieves were collected for the next stage of coating).

[0045] Example 2: Method for preparing a composition of a pharmaceutically active substance having a second release rate: Preparation of the drug coating solution: Guanifacin hydrochloride was added to hydroxypropyl cellulose dissolved in 95% ethanol / pure water to form a coating solution with a solid content of 3.5%.

[0046] Preparation of the isolation layer coating solution: Talc powder was dispersed in 95% ethanol / pure water and homogenized using a homogenizer. Then, it was added to a hydroxypropyl methylcellulose coating solution already dissolved in 95% ethanol, resulting in a solids content of 5.3%.

[0047] Preparation of the sustained-release coating solution: Talc powder was dispersed in 95% ethanol and homogenized using a homogenizer. Then, Eudragit RS100 and triethyl citrate coating solution, which had been dissolved in 95% ethanol, were added, resulting in a solid content of 8%.

[0048] The sucrose pellet cores were added to a fluidized bed and coated using a fluidized bed bottom spray coating process, sequentially applying the top layer coating solution, the isolation layer coating solution, and the sustained-release layer coating solution. After each layer of coating solution was sprayed, it was dried and sieved. The sustained-release layer coating had a weight gain of 15% WG (after drying, the pellets were passed through a 20-mesh sieve and a 60-mesh sieve, and the pellets between the 20-mesh and 60-mesh sieves were collected for the next stage of coating).

[0049] Example 3: Preparation method of guanifacine hydrochloride multifunctional drug release composition: The composition obtained in Example 1 and the composition obtained in Example 2 were uniformly mixed to obtain a multifunctional drug release composition, which was then filled into No. 0 gelatin capsules.

[0050] Example 4: Method for preparing a composition of a pharmaceutically active substance having a first release rate: Preparation of the drug coating solution: Guanifacin hydrochloride was added to hydroxypropyl cellulose dissolved in 95% ethanol / pure water to form a coating solution with a solid content of 2.4%.

[0051] Preparation of the isolation layer coating solution: Talc powder was dispersed in 95% ethanol / pure water and homogenized using a homogenizer. Then, it was added to a hydroxypropyl methylcellulose coating solution already dissolved in 95% ethanol, resulting in a solids content of 8%.

[0052] Preparation of the sustained-release coating solution: Talc powder was dispersed in 95% ethanol and homogenized using a homogenizer. Then, Eudragit RS100, Eudragit L100-55, and triethyl citrate coating solution, which had been dissolved in 95% ethanol, were added, resulting in a solid content of 8%.

[0053] The sucrose pellet cores were added to a fluidized bed and coated using a fluidized bed bottom spray coating process, sequentially applying the top layer coating solution, the isolation layer coating solution, and the sustained-release layer coating solution. After each layer of coating solution was sprayed, it was dried and sieved. The sustained-release layer coating had a weight gain of 9% WG (after drying, the pellets were passed through a 20-mesh sieve and a 60-mesh sieve, and the pellets between the 20-mesh and 60-mesh sieves were collected for the next stage of coating).

[0054] Example 5: Method for preparing a composition of a pharmaceutically active substance having a second release rate: Preparation of the drug coating solution: Guanifacin hydrochloride was added to hydroxypropyl cellulose dissolved in 95% ethanol / pure water to form a coating solution with a solid content of 2.4%.

[0055] Preparation of the isolation layer coating solution: Talc powder was dispersed in 95% ethanol / pure water and homogenized using a homogenizer. Then, it was added to a hydroxypropyl methylcellulose coating solution already dissolved in 95% ethanol, resulting in a solids content of 8%.

[0056] Preparation of the sustained-release coating solution: Talc powder was dispersed in 95% ethanol and homogenized using a homogenizer. Then, Eudragit RS100, Eudragit L100-55, and triethyl citrate coating solution, which had been dissolved in 95% ethanol, were added, resulting in a solid content of 8%.

[0057] The sucrose pellet cores were added to a fluidized bed and coated using a fluidized bed bottom spray coating process, sequentially applying the top layer coating solution, the isolation layer coating solution, and the sustained-release layer coating solution. After each layer of coating solution was sprayed, it was dried and sieved. The sustained-release layer coating had a weight gain of 15% WG (after drying, the pellets were passed through a 20-mesh sieve and a 60-mesh sieve, and the pellets between the 20-mesh and 60-mesh sieves were collected for the next stage of coating).

[0058] Example 6: Preparation method of guanifacine hydrochloride multifunctional drug release composition: The composition obtained in Example 4 and the composition obtained in Example 5 were uniformly mixed to obtain a multifunctional drug release composition, which was then filled into No. 0 gelatin capsules.

[0059] Example 7: Dissolution Experiment Dissolution tests were conducted on the compositions or capsules prepared in Examples 1-6 in hydrochloric acid buffer (pH 2.2) or phosphate buffer (pH 6.8). See attached figures for specific results. Figures 1-3 ,Depend on Figure 1-3 It is evident that the composition and capsules of the present invention possess excellent and unexpected dissolution characteristics. In particular, in Example 6, when a specific sustained-release agent material is selected, the capsules of the present invention can still be released at a high pH value (pH=6.8) for up to 16 hours, achieving excellent technical results.

[0060] The preferred embodiments of the present invention have been described above, but are not intended to limit the invention. Those skilled in the art can make modifications and variations to the embodiments disclosed herein without departing from the scope and spirit of the invention.

Claims

1. An oral pharmaceutical composition, characterized by, The oral composition comprises at least two microspheres: (i) microspheres of guanifacine or a pharmaceutically acceptable salt thereof released at a first rate; and (ii) microspheres of guanifacine or a pharmaceutically acceptable salt thereof released at a second rate and a pharmaceutically acceptable excipient, preferably guanifacine hydrochloride as the pharmaceutically acceptable salt of guanifacine.

2. The oral pharmaceutical composition according to claim 1, characterized in that, The first rate of release is faster than the second rate of release.

3. The oral pharmaceutical composition according to claim 1, characterized in that, The first rate of release of guanifacine accounts for 10% to 50% of the total weight of guanifacine; the second rate of release of guanifacine accounts for 50% to 90% of the total weight of guanifacine.

4. The oral pharmaceutical composition according to claim 1 or claim 2, characterized in that, The second rate of release is a slow-release process.

5. The oral pharmaceutical composition according to claim 1 or claim 2, characterized in that, (i) and (ii) further include at least one excipient.

6. The oral pharmaceutical composition according to claim 5, characterized in that, The excipients are selected from slow-release agents, lubricants, plasticizers, adhesives, or fillers.

7. The oral pharmaceutical composition according to claim 1 or claim 2, characterized in that, At least one of the excipients in (i) and (ii) is a sustained-release agent. Preferably, the sustained-release agent is selected from acrylic polymers such as Eudragit RS100, Eudragit L100-55, Eudragit RL100, Eudragit NE30D / NM30D, Eudragit RSPO or a mixture thereof. The sustained-release polymer is preferably selected from Eudragit RS100, Eudragit L100-55 or a combination thereof.

8. The oral pharmaceutical composition according to claim 1 or claim 2, characterized in that, At least one of (i) and (ii) is an adhesive, preferably selected from hydroxypropyl cellulose and hydroxypropyl methylcellulose.

9. The oral pharmaceutical composition according to claim 1 or claim 2, characterized in that, At least one of the excipients in (i) and (ii) is a plasticizer, preferably selected from triethyl citrate, tributyl citrate, acetylacetic acid citrate, polyethylene glycol, or mixtures thereof.

10. The oral pharmaceutical composition according to claim 1 or claim 2, characterized in that, The outermost layer of the microcapsules (i) and (ii) is a sustained-release layer containing a sustained-release agent. The sustained-release layer coating weight gain in microcapsules (i) is 5%-10% WG, and the sustained-release layer coating weight gain in microcapsules (ii) is 11%-20% WG.

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