WO2022039698A1

WO2022039698A1 - Studies for the preparation of drug formulations by a 3d printing technique

Info

Publication number: WO2022039698A1
Application number: PCT/TR2021/050777
Authority: WO
Inventors: Fusun Acarturk; Hazal Ezgi GULTEKIN; Serdar Tort; Fatma Nur TUGCU DEMIROZ
Original assignee: Gazi Universitesi
Current assignee: Gazi Universitesi
Priority date: 2020-08-20
Filing date: 2021-08-06
Publication date: 2022-02-24
Anticipated expiration: 2023-02-20
Also published as: TR202013151A2

Abstract

The invention relates to an extended release pramipexole tablet which is prepared using a fused deposition modeling three dimensional printing technique. The extended release tablet consists of polyethylene oxide and polymers which copolymer derivative of poly(ethyl acrylate, methyl methacrylate) containing a quaternary ammonium group. There is no excipient except the active substance and the polymers. Said tablet formulation is used for the treatment of Parkinson' s disease.

Description

STUDIES FOR THE PREPARATION OF DRUG FORMULATIONS BY A 3D PRINTING TECHNIQUE

Technical Field

The invention relates to an extended release pramipexole tablet prepared by using a fused deposition modeling technique of the three dimensional printing.

State of the Art

The three dimensional (3D) printing is a process of printing any 3D object designed on a digital platform in a solid form in successive layers. It is used in many fields, and recently, it is very common especially in the field of pharmacy. The most important advantage of the 3D printing technologies in pharmacy is the possibility of a personalized medicine. There are many 3D printing techniques with different mechanism of operation. In the fused deposition modeling (FDM) technique which is widely used and rather economical, a plastic or wax material is extruded through a heated nozzle to obtain a semi-solid material. Then, the material is deposited on a platform layer-by-layer, and the desired solid object is obtained. The most commonly used feeding material in FDM technique is in the filament form. Using FDM technique makes it possible to prepare the desired dosage form in a patient-specific dose and form as well as a patient-specific size and at a time when the patient is in the need thereof.

Parkinson’s disease is a progressive neurodegenerative disorder of the central nervous system that affects 1% of the individuals over 60 years of age, wherein the treatment thereof is difficult. The disorder is caused by loss of brain cells producing dopamine. Numerous active substances are used for the treatment of the disease. The active substance, pramipexole, is one of them. Pramipexole is a selective non-ergo dopamine D2 receptor agonist and is an active substance used in the symptomatic treatment of the Parkinson’s disease.

Description of the Invention

The dose of pramipexole is gradually increased in the treatment of Parkinson’s disease, and the dose increase varies depending on the course of the disease and the patient. Thus, the different doses thereof are needed in the treatment. This active substance is suitable for the personalized medicine as it is used for a disease, such as Parkinson’s disease, in which the treatment dose is important. Therefore, the extended release pramipexole tablets suitable for use once daily are prepared using an FDM 3D printing. The extended and immediate release pramipexole tablet formulations prepared using different and conventional methods and the different dosage forms thereof are present in the literature.

An extended release tablet formulation was prepared using an FDM 3D printing technique, a new drug manufacturing technology. Pramipexole was used as an active substance. The tablet formulation prepared has a 24-hour extended release due to the presence of a polyethylene oxide derivative (PEO N80-POLYOX N80) and the poly(ethyl acrylate, methyl methacrylate) copolymer derivatives containing a quaternary ammonium group (Eudragit RSPO and Eudragit RL100). The tablet formulation prepared is used in the treatment of Parkinson’s disease as it comprises the active substance pramipexole.

The process essentially consists of four steps. The concentrations in the process and examples are expressed in weight/weight (w/w).

Step 1. Preparation of a powder mixture of pramipexole, Eudragit RSPO, Eudragit RL100 and PEO N80 polymers. The powder mixture used for the preparation of the extended release tablet formulations contains a combination of the active substance pramipexole and polymeric carrier. Pramipexole and the polymers are crushed in a mortar and mixed. The acrylate polymers and polyethylene oxide polymers are used as polymeric carrier. The acrylate/ammonium methacrylate copolymers are preferred acrylate polymers. The acrylate copolymers with the tradename of Eudragit RSPO and Eudragit RL100 were chosen for the preparation of the extended release formulations. Eudragit RSPO comprises ethyl acrylate, methyl methacrylate and small amounts of methacrylic acid ester containing a quaternary ammonium group. The ammonium groups present as salts make the polymer permeable. Its INCI name is “Acrylates I Ammonium Methacrylate Copolymer” and its chemical/ IUPAC name is ”Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1 :2:0.1.” EUDRAGIT RL 100 comprises ethyl acrylate, methyl methacrylate and small amounts of methacrylic acid ester containing a quaternary ammonium group. Its INCI name is Acrylates / Ammonium Methacrylate Copolymer and its chemical/IUPAC name is “Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2.”

PEO N80 (Polyox) with a molecular weight of 200 kDA is chosen as a poly(ethylene oxide) polymer. The ratio of Eudragit RSPO, Eudragit RL100 and PEO N80 may differ in this polymer combination. The ratio of the polymers in the final powder mixture is 50- 70% w/w for Eudragit RSPO, 10-20% w/w for Eudragit RL100 and 10-30% w/w for PEO N80. Pramipexole may be between 0.25% and 3% w/w of the total powder mixture when the pramipexole, the active substance, is added to the powder mixture. The powder mixture of pramipexole and the polymers is mixed for 5-15 minutes, preferably for 12 minutes.

Step 2. Transfer of the prepared powder mixture to a filament extruder and obtaining of pramipexole loaded filament by a hot melt extrusion technique: A hot melt extrusion (HME) method is used for the preparation of pramipexole loaded filaments. In HME, the active substance, a thermoplastic polymer and the other excipients (plasticizers, antioxidants, etc.), if needed, are homogenously mixed and heated in an extruder to obtain a soft mixture. Then, the resulting soft mixture is passed through an orifice of a certain diameter, and a granule, cylinder or film is obtained. In this step, the powder mixture prepared in step 1 is loaded into a barrel of a single screw extruder, and pramipexole-containing filaments are prepared at 110-140°C, preferably at 135°C. A pramipexole loaded filament is prepared at a diameter of 1.65-1.80 mm, preferably of 1 .70 mm.

Step 3. Designing of a dosage form of the tablet to be prepared by a computer-aided design program and exporting the obtained design to the software of the 3D printer : The tablets to be printed on the 3D printer are designed to have a thickness of 1 -2 mm, a diameter of 8-12 mm and an infill percentage of 10-100% (the infill percentage may be adjusted in the program to which the printer is connected as desired during printing process), so as to have an optimal extended release. Step 4. Printing of the extended release pramipexole tablets by FDM 3D printer using pramipexole loaded filaments as printer feedstock material: The tablets designed by a 3D computer-aided design program are printed to have a thickness of 1 -2 mm, preferably a thickness of 2 mm, a diameter of 8-12 mm and a rounded shape, so as to have an optimal extended release. In FDM 3D printing process, the extruder temperature of the printer is in the range of 150-220°C, preferably 180°C, and the platform temperature of the printer is in the range of 40-100°C, preferably 40°C.

The extended release pramipexole tablet prepared by FDM 3D printing is characterized by comprising Eudragit RSPO, Eudragit RL100 and PEO N80 polymers as a polymeric carrier. The tablet is 150 mg in total and comprises 4.5 mg of pramipexole and 145.5 mg of a polymeric carrier. When the ratios of polymeric carriers are 60% of Eudragit RSPO, 10% of Eudragit RL100 and 30% w/w PEO N80, the polymeric carrier comprises 87.3 mg of Eudragit RSPO, 14.55 mg of Eudragit RL100 and 43.65 mg of PEO N80 polymer for each tablet. It has an infill percentage of 100%. After crushing, pramipexole and the polymers are mixed in a turbulent powder mixer for 5-15 minutes.

The release profile of the extended release pramipexole tablet prepared using FDM 3D printing is 24 hours. The extended release pramipexole tablet prepared is used once daily.

The following examples illustrate the invention, but is not limiting in anyway.

Example 1 . Preparation of pramipexole-containing filaments

A total of 5 g powder mixture of the active substance pramipexole, Eudragit RSPO, Eudragit RL100 and PEO N80 is prepared before the preparation of pramipexole- containing filaments. 3%, i.e. 150 mg, of the powder mixture consist of pramipexole, and the remaining contains a polymeric carrier. In the polymeric carrier, the ratios of Eudragit RSPO, Eudragit RL100 and PEO N80 are 60:10:30 in w/w, respectively. This ratio is the one which was determined to achieve the optimum extended release formulation. After crushing in a mortar, pramipexole and the polymers are mixed in a turbulent mixer for 12 minutes. The resulting powder mixture is transferred to the barrel of the single screw extruder. The pramipexole loaded filaments are prepared by the hot melt extrusion technique at a temperature of 135°C which is determined to be optimal for that powder mixture. After the process, the resulting filaments have a diameter of about 1.70 mm. Example 2. Design of the tablet to be printed by 3D printer

The tablet to be printed by 3D printer was designed in a 3D computer-aided design program. The tablets were designed to have a thickness of 2 mm, a diameter of 10 mm and a rounded shape, so as to have an optimal extended release.

Example 3. Printing of the extended release pramipexole tablets by FDM 3D printing

The extended pramipexole tablets were printed by FDM 3D printing using pramipexole loaded filaments of Example 1 as a printer feedstock material. The printing process were performed according to the design mentioned in Example 2. In this step, the extruder temperature of the printer was 180°C, the platform temperature of the printer was 40°C, and the printing process was optimally performed at these temperatures. The time period of the printing process was about 4 minutes. The dose of the pramipexole in the extended release pramipexole tablet printed was 4.5 mg. The weight of the tablet was 150 mg, the diameter of the tablet was 10 mm, and the thickness of the tablet was 2 mm. The tablets were printed with an infill percentage of 100% (the infill percentage may be adjusted on the software of 3D printer is connected as desired before the printing process). The layers of the tablet prepared had a thickness of 0.15 mm. The resulting extended release pramipexole tablet released 81% of pramipexole contained therein within 24 hours. Therefore, it exhibited a 24-hour extended release profile and was suitable for use once daily. The extended release pramipexole tablet prepared was administered to male Wistar rats with a body weight of 339±20 g orally by adjusting the dose according to the weight of the rat. In the pharmacokinetic studies, which carried out on rats, a 24-hour plasma profile was obtained. The results obtained from in vivo studies support the results obtained from in vitro studies.

Advantages of the Invention

The technical problems which were solved by the preparation of the extended release pramipexole tablet formulation are summarized in the following: - A tablet formulation was prepared using an FDM 3D printing technique, a new drug production technology, for the treatment of Parkinson’s disease in which personalized medicine is important. - The tablet formulation prepared is suitable for use once daily as it exhibits a 24-hour drug release profile. - It is possible to prepare tablet formulations in different doses of the active substance by 3D printing method. Thus, the purpose of “personalized dosing” of the personalized medicine is achieved when the tablet is prepared using the commercially available and unavailable different doses of pramipexole. - The tablet was prepared using minimum amount of excipients (contains no disintegrant, binder, or plasticizer). Thus, the method of preparing the tablet is economical.

Description of the Figures

Figure 1 . The summary of an FDM 3D printing process.

Figure 2. The design and shape of extended release pramipexole tablet prepared by FDM 3D printing technique.

Figure 3. 24-hour release profile of extended release pramipexole tablet prepared by FDM 3D printing technique.

Figure 4. The plasma pramipexole concentration-time profile of 3D tablet formulation administered to the rats in the dose of 3 mg/kg.

Claims

1 . An extended release pramipexole tablet prepared by using a fused deposition modeling (FDM) three dimensional (3D) printing technique, wherein it comprises Eudragit RSPO, Eudragit RL100 and PEO N80 polymers as polymeric carrier.

2. The extended release pramipexole tablet prepared by using an FDM 3D printing technique according to claim 1 , wherein the polymeric carrier comprises 50- 70% w/w Eudragit RSPO, 10-20% w/w Eudragit RL100 and 10-30% w/w PEO N80 polymers.

3. The extended release pramipexole tablet prepared by using an FDM 3D printing technique according to claim 2, wherein the polymeric carrier comprises 60% w/w Eudragit RSPO, 10% w/w Eudragit RL100, and 30% w/w PEO N80 polymers.

4. The extended release pramipexole tablet prepared by using an FDM 3D printing technique according to claim 1 , comprising 0.25% to 3% (w/w) of pramipexole by weight.

5. The extended release pramipexole tablet prepared by using an FDM 3D printing technique according to claim 1 , wherein a unit tablet has a thickness of 1 -2 mm and a diameter of 8-12 mm.

6. The extended release pramipexole tablet prepared by using an FDM 3D printing technique according to claim 1 , wherein the tablet has a release profile of 24 hours and is used once a day.

7. The extended release pramipexole tablet prepared by using an FDM 3D printing technique according to claim 1 , which is obtained according to the following process: a) Preparing a powder mixture of pramipexole, Eudragit RSPO, Eudragit RL100 and PEO N80 polymers, b) Transferring the resulting powder mixture to a filament extruder, and preparing pramipexole-loaded filaments using a hot melt extrusion technique,

7 c) Designing the tablet to be printed on a 3D printer in a computer-aided 3D design program, d) Printing the extended release pramipexole tablets by an FDM 3D printer using the pramipexole-loaded filaments as a printer feedstock material, A process for obtaining the extended release pramipexole tablet prepared by using an FDM 3D printing technique according to claim 7, wherein in step a), the powder mixture comprising of pramipexole and polymers are mixed for 5-15 minutes. The process for obtaining the extended release pramipexole tablet prepared by using an FDM 3D printing technique according to claim 7, wherein in step b), the pramipexole-loaded filaments are prepared by a hot melt extrusion technique at 110-140°C. The process for obtaining the extended release pramipexole tablet prepared by using an FDM 3D printing technique according to claim 7, wherein in step b) the pramipexole-loaded filament is prepared at a diameter of 1 .65-1 .80 mm. The process for obtaining the extended release pramipexole tablet prepared by using an FDM 3D printing technique according to claim 7, wherein in step d), tablets designed in a computer-aided 3D design program are printed to have a thickness of 1 -2 mm, a diameter of 8-12 mm and a rounded shape, so as to have an extended release. The process for obtaining the extended release pramipexole tablet prepared by using an FDM 3D printing technique according to claim 7, wherein in step d), the tablets are printed on an FDM 3D printer at an extruder temperature of 150- 220°C and a printer platform temperature of 40-100°C.

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