Process for preparing aripiprazole oral soluble film

This application is a divisional of U.S. application Ser. No. 17/087,949, filed Nov. 3, 2020; which claims the priority of Chinese Application No. 202010995622.8, filed Sep. 21, 2020; which is incorporated herein by reference in its entirety.

The present invention relates to an oral soluble film for delivery of aripiprazole. The oral film contains aripiprazole particles in a low micron size and is a crystalline state. The oral film provides rapid dissolution of aripiprazole in mouth and is flexible and uniform in appearance.

Schizophrenia is a common type of mental illness with delusions, hallucinations and complete separation from others. Schizophrenia is more prevalent than Alzheimer's disease, multiple sclerosis, insulin-dependent diabetes, and muscular dystrophy. According to World Health Organization data, schizophrenia continues to have the highest prevalence of any serious mental illness, affecting about 7‰ of adults worldwide.

The earliest antipsychotic drugs such as chlorpromazine, haloperidol, perphenazine, and sulpiride are known as typical or first-generation antipsychotic drugs (FGA). This type of drugs is gradually being replaced by second-generation antipsychotic drugs (SGA). SGA is also known as an atypical antipsychotic drug and is represented by clozapine, olanzapine, and risperidone, which are significantly better than the first-generation antipsychotic drugs in terms of safety and tolerability. However, long-term use of SGA can lead to weight gain and an increased tendency for abnormal lipid and glucose metabolism, thus leading to poor patient compliance with medication.

Aripiprazole, as the world's first partial dopamine agonist, can regulate dopamine levels without completely blocking the dopamine D2 receptor, and is also known as “third-generation antipsychotic drug” (TGA). It has clinical characteristics such as fast onset, high safety and good tolerance while having little effect on the levels of blood glucose, body weight and prolactin, so it can effectively improve the patient's compliance with long-term medication.

The currently marketed dosage forms are mainly ordinary tablets, orally disintegrating tablets, capsules, and long-acting injections. Due to the particularity of the patient population, the swallowing compatibility with ordinary tablets and capsules is poor, which limit patient compliance. As for the orally disintegrating tablets, the disadvantages include complicated preparation process, a large amount of excipients, high cost, low hardness, special packaging, inconvenient transportation and storage, and a grit feeling after oral administration. Long-acting injections have the problems of high production cost, inconvenient transportation and storage, and low patient compliance.

As a new oral drug delivery system, an oral soluble film is convenient to carry and use. It is suitable for patients who have difficulty in swallowing, which improves patient compliance. As a new dosage form, the form is attractive to patients who have difficulties with previously available options. Its unique method of administration can also greatly avoid concealment and vomiting by mental patients, and has advantages in the clinic.

The challenge in developing aripiprazole into an oral film is the low solubility of aripiprazole, content uniformity and discomfort (bitter taste) after film disintegration.

It has been reported that β-cyclodextrin is incorporated into injection solution to improve the solubility. However, the limited drug loading of the oral soluble film is insufficient to achieve the drug required amount.

U.S. Pat. No. 9,694,008 discloses an orally fast dissolving film formulation comprising aripiprazole or a pharmaceutically acceptable salt thereof and an organic acid, wherein: the film formulation has a pH in the range of 4.95 to 5.18; the aripiprazole or the pharmaceutically acceptable salt thereof and the organic acid have a weight ratio in the range of 2:1 to 66:1; the organic acid is citric acid. The '008 patent uses organic acids to control the pH within a narrow range of 4.95 to 5.18 to improve solubility. Such narrow pH range is difficult to control for manufacturing. Different saliva levels of different individuals also influence on the and affect the drug release rate in individuals.

There exists a need for a new and improved oral soluble film of aripiprazole, which achieves ideal dissolution, uniformity, stability, scalability, and patient compliance.

The present invention provides aripiprazole oral soluble film with improved drug dissolution, uniformity, and taste. The inventors have discovered that by controlling the aripiprazole particle size and the crystalline state in the oral film, the film provides a desirable aripiprazole dissolution rate in the oral cavity and a comparable bioavailability to that of an aripiprazole tablet. The film has a good stability and a desirable taste. The aripiprazole oral soluble film is placed in the oral cavity of a subject, dissolved in saliva, and then swallowed and absorbed in the gastrointestinal tract.

The oral soluble film of the present invention uses small particle size of aripiprazole (D 90 : 14.3 μm) to maximize the specific surface area to achieve rapid dissolution, without adding plasticizers, stabilizers, surfactants, or clathrates into the formulation. The production process does not require an organic solvent which improves to environmental protection and safety. Since the particle size is extremely small, the film does not produce a sense of grain and provides a good palatability.

The aripiprazole oral soluble film of the present invention comprises 0.5-70% w/w of aripiprazole in a crystalline state and 25-96% w/w of one or more film-forming materials, wherein 90% of the aripiprazole particles have a size of <14.3 μm and are uniformly blended in the film without visible undispersed particles.

The aripiprazole oral soluble film comprises aripiprazole, or a pharmaceutically acceptable salt thereof, in a small particle size of D 90 being 14.3 μm. “D 90 ” as used herein, means 90% of the particles have a diameter below the recited value. For example, D 90 of 14.3 μm means that 90% of the particles have a diameter below 14.3 μm.

The commercially available aripiprazole typically has a particle size of 65-100 μm. When aripiprazole with a particle size of D 90 : 30 to 100 μm was used to prepare an oral soluble film, the film was non-uniform in appearance due to drug sedimentation during film formation; the film had an unacceptably slow dissolution rate and a grit-like taste when it was dissolved in mouth.

Aripiprazole in the oral soluble film in general is in an amount of about 10-70% w/w, preferably about 10-65%, or about 15-65%, or about 20-65% w/w. The D 90 particle size of aripiprazole in general is about 14 μm, preferably about 12 μm or about 10 μm. “About” as used herein, refers to ±10% of the recited value. About 90% of aripiprazole particles in the oral soluble film have a size distribution of about 0.1-14 μm, about 0.1-12 μm, or about 0.1-10 μm.

Aripiprazole in the oral soluble film of the present invention is in a crystalline state. The inventors have discovered that when the drug substance aripiprazole is in an amorphous form, aripiprazole dissolves in the oral cavity too quickly and results in a bitter taste. Moreover, the stability of aripiprazole is reduced noticeably due to the amorphous form. The present invention combines the features of small particles and crystalline state of aripiprazole and provides an oral film with a good dissolution rate, a palatability, and a uniform and flexible film.

The film-forming materials useful in the pharmaceutical composition include, but not limited to, polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hypromellose (HPMC), sodium carboxymethyl cellulose (CMC-Na), xanthan gum, pectin, copovidone, povidone, guar gum, pullulan, polyethylene oxide, sodium alginate, and chitosan. Preferred film-forming materials are polyvinyl alcohol, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, copovidone, povidone, pullulan, polyethylene oxide. More preferred film-forming materials are polyvinyl alcohol, hypromellose, hydroxypropyl cellulose, and hydroxyethyl cellulose. The weight percentage of film-forming materials is about 25-96%, 30-96%, 35-96%, 25-80%, 30-80%, or 35-80% w/w. The film-forming materials are compatible with aripiprazole and provide a suitable drug loading capacity.

In one embodiment, the film of the present invention further comprises a defoamer to improve the defoaming efficiency of film-forming solution and flexibility of the film. In general, the defoamer is in an amount of about 0.01-10% or 0.02-5% w/w, preferably about 0.05-5%, about 0.05-2%, about 0.05-1%, or about 0.1-0.5% w/w. In one embodiment, the defoamer is selected from the group consisting of dimethicone, simethicone, oleyl alcohol, and a combination thereof.

One or more coloring agents are optionally added to the film-forming materials to improve the color of the oral soluble film. The coloring agent, for example, are selected from the group consisting of FD&C colors, D&C colors, and combinations thereof.

One or more flavoring agents or taste masking agents are optionally added to improve the taste of the oral soluble film. The flavoring agent may include one or more ingredients as follows: sucrose, glucose, sodium saccharin, fructose, xylitol, stevia , aspartame, sucralose, neotame and acesulfame potassium, peppermint oil, menthol, orange flavor, pineapple flavor, cherry flavor, apple flavor, banana flavor, blueberry flavor, peach flavor, mango flavor, or grape flavor. Sucralose and menthol are preferred flavoring agents for the present invention. The amount of a flavoring agent in the composition is about 0.01-5%, preferably about 0.05-2% (w/w) in the film forming solution and in the film.

The oral film of the present invention does not include a plasticizer or a surfactant. Plasticizer are typically used to improve the flexibility of a film, and surfactants are typically used to increase the solubility of aripiprazole. Because the present invention uses small particles (D 90 : 14 μm) of aripiprazole, the film forming solution has a good solubility of aripiprazole, and the film has a good flexibility without a plasticizer or a surfactant.

The oral film of the present invention does not include an organic solvent. Organic solvents are sometimes used to improve the solubility of aripiprazole. Because the present invention uses small particles (D 90 : 14 μm) of aripiprazole, the film forming solution has a good solubility of aripiprazole without an organic solvent. In one embodiment, the oral film further does not include an organic acid such as citric acid.

The present invention is also directed to a process for preparing the aripiprazole oral soluble film. The process comprises the steps of: (a) grinding a starting material of aripiprazole by bead milling, air crushing, or colloid milling until 90% of the aripiprazole particles have a size of ≤14.3 μm, (b) blending the aripiprazole particles of (a) and one or more film-forming materials in an aqueous solution by a mechanical homogenization blending process at a speed of at least 1500 rpm, optionally further by plate- and frame blending, to prepare a uniform suspension, (c) defoaming the suspension; and (d) coating the defoamed suspension on a substrate and drying the suspension to form the film.

In step (a), a starting material of aripiprazole (typically having D 90 of 50-100 μm) was grinded until the aripiprazole particles reach desirable smaller sizes of D 90 : 14.3 μm and maintain a crystalline state. Normal tooth mill, knife mill and high-pressure homogenization processes cannot obtain the required particle size, while bead milling, air-guided crushing and colloidal milling processes can reduce the particle size D 90 to 14.3 μm and maintain the original crystal form. A preferred mill process is bead milling with a scatter axis speed of ≥3000 rpm (e.g., 3000-6000 rpm) and milling cycles ≥3 cycles.

The issues of aripiprazole including slow dissolution rate, grit-like taste and stability problems can be resolved by a special milling process, but due to the strong electrostatic adsorption of small aripiprazole particles, they tend to adsorb together and aggregate into agglomerates. Furthermore, aripiprazole is a poorly soluble non-ionic compound, especially in the case of fine particle size with a large surface tension, it is difficult to have a even suspension. Step (b) resolves these problems.

In step (b), the aripiprazole particles of smaller sizes, one or more film-forming materials, and optionally a defoamer are blended in an aqueous solution by homogenization blending to prepare a uniform film-forming suspension. Different blending processes can lead to different blending uniformity. The conventional paddle blending, plate and frame blending, and paddle blending plus plate-and-frame blending do not achieve the required blending uniformity. However, homogenization blending or homogenization blending plus plate-and-frame blending fully disperses the aripiprazole crystal particle agglomerates to form a uniform suspension, without a need to add surfactants or emulsifiers. To form a homogeneous suspension, a preferred homogenization speed is at least 1500 rpm (e.g., 1500-4000 rpm or 1500-3000 rpm) and preferred homogenization time is at least 3 minutes (e.g., 3-20 minutes). Conduct a defoaming process to obtain the homogeneous film forming solution.

In step (c), the blended suspension of (b) is defoamed. In the formulation, aripiprazole is in the crystalline form with a high specific gravity, which leads to sedimentation during the defoaming process. Although, adding a suspending agent or thickening agent can slow down the settling rate, it also prolongs the defoaming time. Therefore, defoaming agents, which increase the surface tension and accelerate the bursting of bubbles, are preferably used together with vacuum defoaming technique to reduce the defoaming time. With preferred defoaming agents (e.g., dimethicone, simethicone, or oleyl alcohol) and vacuum defoaming process, the defoaming time is shortened by more than 8 h, while the film-forming ability and stability of the film is maintained. A defoaming agent may further hinder the sedimentation of aripiprazole, while improving the production efficiency and reducing production costs.

In step (d), the defoamed suspension is coated on a substrate such as a conveyer and is dried to form a film. The dried film is ready to be cut and packaged.

The advantages of the oral soluble film of the present invention are summarized below:

a. As the aripiprazole remains original crystal form and degree of crystallinity, the stability of the drug substance is maintained and no extra stabilizer is required in the formulation. b. The dissolution rate of aripiprazole is increased dramatically: 85% or even 95% is dissolved within 5 minutes. c. Due to the small particle size of the drug substance, the sedimentation of aripiprazole during the solution preparing, defoaming, coating and drying processes is effectively reduced. Thus, desired uniformity can be achieved in the final film product. d. Combining with a homogenization process, the drug load percentage is improved to 60% w/w without using any plasticizer. e. As the particle size of the drug substance is extremely small, no grit-like taste or any other uncomfortable feeling develops after the film is dissolved in the oral cavity, which improves taste. f. The oral soluble film formed is flexible and not brittle without the use of plasticizers.

The following examples further illustrate the present invention. These examples are intended merely to be illustrative of the present invention and are not to be construed as being limiting.