Solid pharmaceutical dosage formulations and processes

Abstract

A process for producing a solid pharmaceutical dosage formulation, said process comprising powder bed fusion selective laser 3-dimensional printing of a mixture comprising: (a)a drug; and (b)an excipient; whereinat least one of said drug and said excipient absorbs electromagnetic radiation at a wavelength emitted by the laser; or (a)a drug; (b)an excipient; and (c)an absorbent material which absorbs electromagnetic radiation at a wavelength emitted by the laser.

Claims

1. A process comprising: powder bed fusion selective laser 3-diminsional printing of a powder mixture comprising: (a) a drug; and (b) an excipient; wherein at least one of said drug and said excipient absorbs electromagnetic radiation at a wavelength emitted by the laser; or (a) a drug; (ab) an excipient; and (c) an absorbent material with absorbs electromagnetic radiation at a wavelength emitted by the laser, the absorbent material selected from the group consisting of iron oxide, titanium oxide, silicates, carmine, candurin, phtalacyanine, diazos, or mixtures thereof; and producing an oral formulation to the exclusion of a surgically inserted implant.

2. The process as claimed in claim 1, wherein said powder bed fusion selective laser 3-dimensional printing comprises selective laser sintering 3-dimensional printing or selective laser melting 3-dimensional printing, or a mixture thereof.

3. The process as claimed in claim 1 wherein said excipient absorbs electromagnetic radiation at a wavelength emitted by the laser.

4. The process as claimed in claim 1 wherein said electromagnetic radiation is electromagnetic radiation within the infrared, visible or ultraviolet regions of the electromagnetic spectrum.

5. The process as claimed in claim 1 wherein the laser power is at least 1.5 W.

6. The process as claimed in claim 1 wherein said mixture is a heterogeneous mixture.

7. The process as claimed in claim 1 wherein the laser emits electromagnetic radiation having a wavelength in the range of from 200 nm to 11 μm without degradation of the drug.

8. The process as claimed in claim 1 wherein said printing is performed using a scan speed in the range of from 20 mm/s to 300 mm/s; and/or wherein said printing is performed using a surface temperature in the range of 40-180° C.

9. The process as claimed in claim 1 wherein said mixture comprises from 0.01 wt. % to 85 wt. % of the said drug by total weight of the mixture.

10. The process as claimed in claim 1 wherein said mixture comprises two or more excipients; and/or wherein said mixture comprises from 15 wt. % to 99.5 wt. % of the said excipients by total weight of the mixture.

11. The process as claimed in claim 1 wherein the said excipient comprises or consists of a polymer; optionally wherein said polymer comprises at least one enteric polymer; or wherein said polymer comprises at least one pH-independently soluble polymer; and/or wherein said polymer has a glass transition temperature in the range of from −100° C. to 250° C.

12. The process as claimed in claim 11 wherein said polymer is selected from the group consisting of methyl acrylate-methacrylic acid copolymers, ethyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate, methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate trimellitate, sodium alginate, zein, polyethylene oxide, ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers, gelatin, polysaccharides and mixtures thereof.

13. The process as claimed in claim 1 wherein said mixture comprises from 0.1 wt. % to 50 wt. % of the said absorbent material by total weight of the mixtures.

14. The process as claimed in claim 1 wherein said mixture comprises: (a) 1-50 wt. % of a drug selected from anti-inflammatory, steroid or antieoplastic drugs by total weight of the mixture, (b) 20-80 wt. % of an enteric polymer selected from methyl acrylate-methacrylic acid copolymers, ethyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate, methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate trimellitate, sodium alginate, zein, polyethylene oxide, ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers, gelatin, polysaccharides and mixtures thereof, by total weight of the mixture; and (c) 0.1-30 wt. % of at last one absorbent material selected from the group consisting of iron oxide, titanium oxide, silicates, carmine, candurin, phthalocyanine, diazos or mixtures thereof, by total weight of the mixture.

15. A solid pharmaceutical dosage formulation produced by the process of claim 1; said solid pharmaceutical dosage formulation optionally having a laminated core comprising multiple layers, each layer comprising: (a) a drug, (b) an excipient, and (c) optionally an absorbent material selected from the group consisting of iron oxide, titianium oxide, silicates, carmine, candurin, phtalacyanine, diazos, or mixture thereof.

16. The solid pharmaceutical dosage formulation of claim 15 wherein said solid dosage formulation is bioadhesive and/or mucoadhesive.

17. A solid pharmaceutical dosage formulation, the surface of which comprises a drug and a sintered polymer and/or sintered absorbent material.

18. The solid pharmaceutical dosage formulation of claim 17 wherein said drug is suspended in a matrix comprising: (a) An excipient which absorbs electromagnetic radiation at a wavelength of 380 nm to 800 nm; or (b) an excipient; and (c) an absorbent material selected from the group consisting of iron oxide, titanium oxide, silicates, carmine, candurin, phtalocyanine, diazos, or mixtures thereof, which absorbs electromagnetic radiation at a wavelength of 380 nm to 800 nm.

19. The solid pharmaceutical dosage formulation claim 15 having a laminated core comprising multiple layers, each layer comprising: (a) a drug, (b) an excipient, and (c) optionally an absorbent material selected from the group consisting of iron oxide, titanium oxide, silicates, carmine, candurin, phtalocyanine, diazos, or mixtures thereof.

20. A process comprising: powder bed fusion selective laser 3-diminensional printing of a powder mixture comprising (a) a drug; and (b) an excipient; wherein at least one of said drug and said excipient absorbs electromagnetic radiation at a wavelength emitted by the laser; or (a) a drug; (ab) an excipient; and (c) an absorbent material which absorbs electromagnetic radiation at a wavelength emitted by the laser, the absorbent material selected from the group consisting of iron oxide, titanium oxide, silicates, carmine, candurin, phtalocyanine, diazos, or mixtures thereof; and producing an oral formulation having a controlled release of the drug.

Description

BRIEF DESCRIPTION OF FIGURES

(1) FIG. 1: Schematic of Powder Bed Fusion Selective Laser 3DP Methods

(2) FIG. 2: Schematic of SLS 3DP

(3) FIG. 3: typical 3DP geometries

(4) FIG. 4: 3DP geometries from examples

(5) FIG. 5: 3DP geometries from examples

(6) FIG. 6: Drug release results for example formulations

(7) FIG. 7: SEM Micrographs of Kollicoat IR+Mannitol+Paracetamol+Colourant as absorbant material (71%/20%/5%/3%) at different laser scan speeds

(8) FIG. 8: Cardurin colourants used as absorbent material under the previously detailed testing conditions show high absorbance (>0.2) at 445 nm. PVA polymer shows absorbance lower than 0.01 (PVA cannot be sintered). Mixtures of PVA and different concentrations of Candurin Gold (colourant) show absorbance values higher than 0.01 and the mixtures can be sintered to obtain oral dosage forms.

(9) FIG. 9: Absorbance values of some polymers and the drug paracetamol under the same conditions. Shellac has an absorbance higher than 0.01 at 445 nm and it can be sintered without using any other absorbent material

(10) FIG. 10: Kollidon VA-64 0.1 mm diameter pellets

(11) FIG. 11: Polypill containing paracetamol and salicylic acid in two different layers

(12) FIG. 12: 80% paracetamol loaded tablet according to example 8

(13) FIG. 13: Tablets made of PEO 100 KDa containing the drug 4-ASA printed with three different laser scanning speeds. From left to right: 200, 300, 400 mm/s

EXAMPLES

(14) A desktop SLS printer from Sintratec (Sintratec Kit, Switzerland) with a blue diode laser of 2.3 W was used.

(15) TABLE-US-00003 TABLE 3 Comparison of Sintratec printer with other SLS printers Printer Sintratec Other printers Laser type Blue diode Laser CO2 laser, infrared light Laser power 2.3 W 2 to 140 W Wavelength 445 nm 9.4 to 10.6 μm Surface temperature 80 to 180° C. — Chamber temperature 60 to 150° C. — Scan speed 30 to 200 mm/s. 1270-12700 mm/s Beam spot size 0.2 mm —

(16) In the examples the sintering process is promoted by the use of colourants as absorbent materials. These absorb the laser energy more efficiently. The use of a colourant is not a requirement if the drug or excipient absorbs light at the right wavelength. The inventors have evaluated different colourants used in the pharmaceutical industry e.g. Iron oxide or Carmine, Cardurin Orange (Merck, UK), which showed very good performance.

(17) A polymer was used as excipient, having a relatively low transition glass temperature (Tg) and a colourant was used as absorbent material. 3% of colourant was used with, for example, polymers including Eudragit L-100-55, Kollidon VA-64, Kollicoat IR and Polyethylene oxide.

(18) Drug release tests in biorelevant media have been used to demonstrate drug release profiles which can be varied dependent on the polymer composition of the tablets or films and associated methodologies. For example it is possible to achieve immediate release of the drug (or drugs) using formulations incorporating Kollicoat IR and to achieve modified release for cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose and acrylic polymers such as Eudragit L100.

(19) For example, it has proved possible to achieve very rapid disintegration by creation of films prepared with polyethyleneoxide.

(20) SLS 3DP has also been used to generate formulations which can adhere to surfaces (such as the inside of the mouth) i.e. are bioadhesive or mucoadhesive, and allow gradual drug release in that environment.

(21) Examples of drug release profiles from several formulations are shown in FIG. 3.

(22) Results to date highlight for the first time the potential of SLS 3D printing to fabricate solid dosage forms such as oral tablets, buccal films and topic masks with defined drug release characteristics and in principle will allow the use of SLS 3D printing of appropriate excipients for manufacture of medicines with doses which are tailored to the patient. This productive system could be also adapted to the industrial scale for production of medicines avoiding other manufacturing methods as tableting or processing drawbacks as large batch productions.

Example 1: Preparation of Drug-Loaded Printed Pharmaceutical Dosage Formulations by SLS 3DP

(23) A mixture of excipient, absorbent material and 5% paracetamol was prepared using a mortar and pestle. Paracetamol was used as a model drug. A polymer excipient having a relatively low glass transition temperature (Tg) was used in combination with a colourant (3-10%) as the absorbent material. Some of the polymers successfully tested include Eudragit L-100-55, Kollicoat IR and Polyethylene oxide.

(24) TABLE-US-00004 TABLE 4 Formulations printed by SLS % PRINTING PARAMETERS Absorbent Laser material Chamber Surface scan (Gold % Drug Temp in Temp speed in Excipient Colourant) (Paracetamol) ° C. in ° C. mm/sec PVA 87-89% 3 5 170 150 110 HYDROLISED (MW 13-23 Kda) PVA 87-90% HYDR. 3 5 170 150 70 (MW 30-70 Kda) PVA NIPPON 3 5 130 95 60 GOHSEI KOLLICOAT IR (PEG 3 5 120 90 90 25% + PVA 75%) KOLLICOAT 3 5 120 90 90 PROTECT (KOLLICOAT IR + PVA) PVA 87-89% 3 5 160 140 110 HYDROLISED (MW 13-23 Kda) + MANNITOL (50/50) PVA 87-89% 3 5 150 130 110 HYDROLISED (MW 13-23 Kda) + MANNITOL (35/65) PVA NIPPON + PEO 4 5 135 120 64 7M (80/20) KOLLICOAT IR + 3 5 120 94 100 MANNITOL (80 + 20) KOLLICOAT IR + 3 5 130 120 150 MANNITOL (60 + 40) KOLLICOAT IR + 3 5 130 100 70 MANNITOL SIGMA (80/20) KOLLICOAT IR + 3 5 130 100 200 MANNITOL SIGMA (60/40) EUDRAGIT L100-55 3 5 120 80 80 EUDRAGIT RS PO 3 5 65 54 70 EUDRAGIT RL PO 3 5 65 54 70 EUDRAGIT FS100 3 5 65 52 100 EUDRAGIT S100 10 5 130 100 55 EUDRAGIT L100 5 5 130 100 60 EUDRAGIT L100-55 + 3 5 85 60 45 PEO 600 Kda (70/30) EUDRAGIT L100-55 + 5 5 90 60 40 PEO 7M (90/10) EUDRAGIT L100-55 + 5 5 90 60 40 PEO 7M (95/5) EUDRAGIT L100-55 + 5 5 140 115 60 PEO 7M (90/10) EUDRAGIT L100-55 + 5 5 140 115 60-75 PEO 7M (90/10) EUDRAGIT L100-55 + 5 5 135 115 70 PEO 7M (80/20) EUDRAGIT L100-55 + 5 5 140 115 60 PEO 7M (90/10) DOUBLE LAYER HPMC ASHLAND 3 5 140 160 100 BENECEL K100LV PH PRM HPMC ASHLAND 3 5 140 166 100 BENECEL K4M PHARM CR MC BENECEL 3 5 140 166 101 A15LV PH PRM HEC HERCULES 3 5 100 125 80 NATROSOL Pharm 250M PHARM HPC KLUCEL 6 5 100 130 75 ASHLAND LF PHARM HPC KLUCEL 3 5 100 130 35 ASHLAND EF PHARM HPC KLUCEL 3 5 100 135 38 ASHLAND MF PHARM HPC KLUCEL 6 5 100 130 75 ASHLAND GF PHARM CELLULOSE 3 5 120 100 100 ACETATE ALDRICH 39.8% ACETYL CONTENT MW 30000 ETHYLCELLULOSE 3 5 130 105 85 DOW ETHYLCELLULOSE 3 5 130 109 50 ALDRICH 46 Cp ETHYLCELLULOSE 3 5 130 100 93 (AQUALON EC-N7) ETHYLCELLULOSE 3 5 130 100 70 ACROSS CP 10 ETHYLCELLULOSE 3 5 125 105 90 ACROSS 10 cps + PEO 7M (90/10) AQOAT AS-LG SHIN 3 5 130 100 90 ETSU AQOAT AS-MG SHIN 3 5 130 100 90 ETSU AQOAT AS-HG SHIN 3 5 130 100 90 ETSU AQOAT AS-MG + 3 5 125 105 120 PEO 7M (90/10) POLYOX 100 Kda 3 5 55 35 100 POLYOX N-12 K 3 5 55 33 35-70 PEO 8M SIGMA 3 5 60 40 35 PEO 300 KDa + 1.5 5 70 55 30 SHELLAC SSB 55 (50/50) PEO 300 KDa + 3 5 50 36 150 KOLLIPHOR P188 (50/50) PEO 300 KDa + 3 5 65 50 35-70 EUDRAGIT RS PO (50/50) SHELLAC WAX- None 5 60 50 125 FREE SIGMA SHELLAC SSB 55 None 5 60 50 50 SHELLAC SSB 55 + None 5 55 40 40 PVA NIPPON (60/40) SHELLAC SSB 55 + None 5 62 54 18 PVA NIPPON (50/50) SHELLAC SSB 55 + 1.5 5 60 40 20 KOLLICOAT IR (50/50) SHELLAC SSB 55 + None 5 70 50 29 XANTHAN GUM (50/50) SHELLAC SSB 55 + 1 5 70 60 60 EUDRAGIT RS PO (50/50) SHELLAC SSB 55 + None 5 75 60 19 MANNITOL (70/30) PVP 40000 MW 3 5 150 120 50 SIGMA PVP 10000 MW 3 5 150 120 130 SIGMA PVP360000 MW 3 5 160 150 70 SIGMA PVP SIGMA 360 KDa + 3 5 PEO 7M (90/10)

(25) A standard desktop SLS 3D printer Sintratec (Sintratec Kit, Switzerland) was used to fabricate the pharmaceutical dosage forms from the mixture. This SLS printer uses a laser of 445 nm wavelength (2.3 W potency) to sinter the powder.

(26) The mixture must include a material that absorbs at the wavelength of the laser in order for the sintering process to take place without degradation of the drug. This can be achieved by having a drug and/or excipient which absorbs in the appropriate region, and/or using an absorbent material.

(27) These examples use a colourant as absorbent material. We have evaluated different colourants used in the pharmaceutical industry e.g. Iron oxide or Carmine, and Cardurin Orange (Merck, UK).

(28) The templates used to print the formulations were designed with AutoCAD 2014® (Autodesk Inc., USA) and exported as a stereolithography file (.stl) into the 3D printer software. The printer settings (temperature of the chamber and laser speed) were selected depending on the characteristics of the polymer excipient.

(29) The basic selected 3D geometries were a cylinder shape tablet (10 mm length×5 mm diameter) and a square patch/film (20 mm length). It was possible to manufacture different types of drug-loaded dosage forms, including tablets of different shapes, films that could be used for buccal delivery, and topical delivery patches.

Example 2: Determination of Drug Loading

(30) Tablets weighing approx. 300 mg, prepared as in example 1, were placed in a volumetric flask with deionized water (1 L) under magnetic stirring until complete dissolution.

(31) Samples of the solutions were then filtered through 0.45 μm filters (Millipore Ltd, Ireland) and the concentration of drug determined with high performance liquid chromatograph (HPLC). We used a Hewlett Packard 1050 Series HPLC system, Agilent Technologies, UK. The validated high performance liquid chromatographic assay entailed injecting 20 μL samples for analysis using a mobile phase, consisting of gradient system of (A) water adjusted to pH 2 with orthophosphoric acid and (B) acetonitrile, through a Luna 5 μm C18 column, 150×4.6 mm (Phenomenex, UK) maintained at 40° C. The mobile phase was pumped at a flow rate of 1 mL/min under the following gradient program: 0-15 min, 5-20% B; 15-16 min, 20-5% B.

(32) HPLC results showed there was no drug degradation during the printing process.

Example 3: Dissolution Test of the Tablet

(33) The drug release performance from the tablets produced according to example 1 was evaluated using a USP-II apparatus (Model PTWS, Pharmatest, Germany). The tablets were placed for 2 h into 750 mL of 0.1 M HCl and subsequently into 1000 mL of 0.05M phosphate buffer (pH 6.8). The paddle speed of the USP-II was fixed at 50 rpm and the tests were conducted at 37+/−0.5° C. The percentage of drug released from the tablets was determined using an in-line UV spectrophotometer (Cecil 2020, Cecil Instruments Ltd., UK) at 244 nm. Data were processed using Icalis software (Icalis Data Systems Ltd, UK).

(34) Drug release profiles from the different formulations show a wide variety of dissolution profiles depending on the composition of the formulations (see FIG. 6). Burst release is shown for some formulations while controlled-release is shown for another.

(35) The selection of the printing parameter, e.g. laser speed or temperature, affects the drug release from the 3D printed formulations. FIG. 7 shows SEM micrographs of Kollicoat IR+Mannitol+Paracetamol+gold colourant as absorbant material (71%/20%/5%/3%) at different laser scan speeds. Formulations are shown in table 5 below.

(36) TABLE-US-00005 TABLE 5 Formulations of tablets shown in FIG. 7 PRINTING PARAMETERS % Absorbant Para- CHAMBER SURFACE LASER Dissolu- Material (Gold ceta- TEMP TEMP SPEED tion time Excipients Colourant) mol (° C.) (° C.) (mm/sec) (min) KOLLICOAT IR + 3 5 120 94 200 0.5 MANNITOL + PARACETAMOL (71/20/5) KOLLICOAT IR + 3 5 120 94 600 5 MANNITOL + PARACETAMOL (71/20/5)

Example 4: Disintegration Test of the Films

(37) The disintegration test performance of the films made according to example 1 was evaluated using a Petri dish placed on a moving surface (Plate shaker IKA, UK) at 50 rpm. The films were placed in 5 mL of deionised water and the time that the film took to undergo disintegration was recorded.

(38) The disintegration time was dependent on the excipient and on the printing temperatures, ranging from 30 s (Polyethylene oxide) to more than 1 h (Eudragit L100-55).

Example 5: Measurement of Absorbance

(39) Absorbance of the drug and/or excipient and/or absorbent material which absorbs electromagnetic radiation at a wavelength emitted by the laser may be measured by spectroscopy. For example, UV-Vis-NIR spectrophotometers are available from manufacturers including Shimadzo (e.g. UV-2600, UV-2700). Absorbance, such as at wavelengths between 200-1400 nm, can be measured by UV-Vis-NIR spectroscopy at room temperature (approximately 25° C.) using a reflecting chamber. “Diffuse Reflectance Accessory(DRA)”.

(40) Here 0.15 g of material to be evaluated (e.g. polymers or mixture of polymer and drug) is blended with 0.5 g of barium sulphate that is compressed and introduced in the spectrophotometer. FIGS. 8 and 9 show measurements under these conditions

(41) In FIG. 8 Cardurin colorants used as absorbent material under the previously detailed testing conditions show high absorbance (>0.2) at 445 nm. PVA polymer shows absorbance lower than 0.01 (PVA cannot be sintered). Mixtures of PVA and different concentrations of Candurin Gold (colorant) show absorbance values higher than 0.01 and the mixtures can be sintered to obtain oral dosage forms.

(42) FIG. 9 shows absorbance values of some polymers and the drug paracetamol. Shellac has an absorbance higher than 0.01 at 445 nm and it can be sintered without using any other absorbent material.

Example 6: Preparation of Drug-Loaded Pellets Printed by SLS

(43) Pellets of 1 mm diameter were prepared using 92% Kollidon VA-64, 5% Paracetamol, 3% Candurin Gold Sheen (FIG. 10). Laser scanning speed was 100 mm/s, chamber temperature 80° C. and surface temperature 100° C.

Example 7: Preparation of Drug-Loaded Polypills Printed by SLS

(44) Polypills made with layer of different composition were prepared containing different drugs (FIG. 11)

(45) The composition of the layers of the polypill is:

(46) Top layer (red): 92% Kollidon VA-64, 5% Salicylic Acid, 3% Candurin red sparkle—Laser scanning speed was 100 mm/s, chamber temperature 80° C. and surface temperature 100° C. Bottom layer (yellow): 92% Kollidon VA-64, 5% Paracetamol, 3% Candurin gold sheen—Laser scanning speed was 100 mm/s, chamber temperature 80° C. and surface temperature 100° C.

Example 8: Preparation of Tablets Incorporating High Drug Loading Printed by SLS

(47) Tablets incorporating 80% paracetamol were prepared using 17% Eudragit L100-55 and 3% Candurin gold sheen (FIG. 12). Laser scanning speed was 90 mm/s, chamber temperature 90° C. and surface temperature 110° C.

Example 9: Preparation of Tablet Incorporating 4-ASA Printed by SLS Highly (FIG. 12)

(48) Tablets prepared with the drug 4-ASA were successfully printed with three different laser scanning speeds (200, 300, 400 mm/s) (FIG. 13). Composition of the tablet: 92% PEO 100 KDa, 5% 4-ASA, 3% Candurin Gold sheen. Chamber temperature was 35° C. and surface temperature 50° C.

(49) HPLC drug loading studies have been performed. No degradation of the 4-ASA drug was found to have taken place during the printing process using SLS. This is a significant advantage compared to FDM printing that was found to degrade the drug 4-ASA while printing. (Goyanes et al. 3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets. Eur. J. Pharm. Biopharm. 89, 157-162).

(50) Conclusions

(51) It was possible to produce with SLS 3DP a great variety of formulations (tablets, films or patches) pre-loaded with drugs and suitable for use as pharmaceutical dosage formulations.

(52) The formulations show a wide variety of dissolution rates (for tablets) and disintegration speeds (for films) that depends on the composition of the formulations.