3D-printed sustained release tablets of a highly water-soluble drug using layered double hydroxide-based ink and a process thereof

Abstract

ABSTRACT: The present invention relates to a 3D-printed sustained release tablet formulation of a highly water-soluble drug and a process for preparing the same using layered double hydroxide (LDH)-based ink. The tablet formulation is prepared by semisolid extrusion and comprises tramadol hydrochloride-loaded Mg-Al-layered double hydroxide (Mg-Al-LDH), hydroxypropyl methylcellulose (HPMC) as a binder and ethanol as a liquid medium. The tablets exhibit prolonged release of tramadol hydrochloride, making them suitable for sustained drug delivery. Additionally, the formulation can be coated with a protective film made of ethyl cellulose and polyethylene glycol. The ink for 3D printing of each tablet is composed of 850 to 900 mg of tramadol hydrochloride-loaded Mg-Al-LDH, 40 to 45 mg of HPMC and 2 to 3 mL of 75%v/v aqueous ethanol. The preparation process involves intercalating tramadol hydrochloride into the Mg-Al-LDH structure, formulating the ink, printing the tablets and coating them. The drug content in the dried tramadol hydrochloride-loaded Mg-Al-LDH is 11.0 to 12.0 weight percentage. This invention offers a novel approach for producing sustained release tablets.

Specification

Description:DESCRIPTION:
Field of the invention:
[0001] The present disclosure generally relates to the technical field of pharmaceutical technology and more specifically, relates to a method for preparing sustained release tablets of a highly water-soluble drug using a 3D printing process, which utilizes layered double hydroxide (LDH)-based ink for producing tramadol hydrochloride-loaded tablets by semisolid extrusion.
Background of the invention:
[0002] Oral drug delivery is the most common and preferred route of administration due to its ease of use and high patient compliance; however, immediate-release formulations often require frequent dosing, especially for drugs with short biological half-lives like tramadol hydrochloride, leading to fluctuations in plasma drug concentration that result in suboptimal therapeutic outcomes. These fluctuations increase the risk of side effects, reduce patient compliance and necessitate frequent dosing to maintain therapeutic levels. To address these issues, sustained release formulations were developed to deliver the drug at a controlled rate, maintaining consistent drug levels in the bloodstream for extended periods. Despite their advantages, traditional manufacturing methods for sustained release, such as matrix formulations, hydrophilic gel systems, or osmotic pumps, can be complex, costly, difficult to scale and not easily adaptable to sensitive formulations or specific patient needs.

[0003] Advancements in 3D printing have opened new possibilities in pharmaceutical manufacturing, allowing for the production of highly customized dosage forms with precise control over drug release. 3D-printed tablets offer several advantages over conventional methods, such as personalized medicine, precision in drug loading and distribution, the ability to achieve complex release profiles by controlling the tablet's internal structure and composition and flexibility in formulation for various drugs and excipients. However, the application of 3D printing technology to sustained-release formulations for specific drugs like tramadol hydrochloride remains underexplored. The intercalation of drugs into layered double hydroxides (LDH), particularly Mg-Al-LDH, provides a promising mechanism for sustained release, as these materials offer a controlled-release matrix that modulates drug release through ion exchange and dissolution processes, protecting the drug and enabling controlled release over time.

[0004] Layered double hydroxides (LDH) have been used in drug delivery systems due to their ability to intercalate active pharmaceutical ingredients between their layers, creating a slow-release mechanism; however, most studies and patents focus on conventional tablet manufacturing processes, limiting flexibility and precision in designing dosage forms. Semisolid extrusion technology has emerged as a promising 3D printing technique for pharmaceuticals, enabling the use of high-viscosity inks that can be precisely deposited layer by layer. Despite its potential, challenges remain in developing printable formulations that ensure proper drug release, stability and mechanical strength.

[0005] An Indian patent (Patent Number:409611- An enteric coated and sustained release oral tablet formulation of diclofenac sodium and a process thereof, which is incorporated by reference herein in its entirety) disclosure provides enteric coated sustained release tablet formulation of diclofenac sodium and a process of preparation thereof, using layered double hydroxide. However, the 3D printing process, the use of tramadol hydrochloride, the specific binder (hydroxypropyl methylcellulose) and the liquid medium (ethanol) are key novel aspects. Further, the formulation involves non-obvious improvements, such as the use of 3D printing to achieve precise drug dosage, optimization of the Mg-Al-LDH intercalation for tramadol hydrochloride and the development of a custom LDH-based ink formulation for sustained release of a highly water-soluble drug. The overall process of developing a 3D-printed sustained-release system with a specific drug and optimized excipients demonstrates inventive steps not apparent from the prior art.

[0006] The present invention offers a novel, customizable and scalable solution for manufacturing sustained release tablets using 3D printing technology. By using tramadol hydrochloride-loaded Mg-Al-layered double hydroxides (MG-Al-LDH) ink and using advanced printing techniques, the invention achieves precise control over drug release, reduces dosing frequency and improves patient compliance. This approach also opens the door for personalized medicine, where dosage forms can be tailored to individual patient needs based on their specific therapeutic requirements.



Objectives of the invention:
[0007] The primary objective of the present invention is to provide a 3D-printed sustained release tablet formulation for sustained release of tramadol hydrochloride, using Mg-Al-layered double hydroxide (Mg-Al-LDH)-based ink; containing Mg-Al-LDH as the drug carrier, hydroxypropyl methylcellulose (HPMC) as a binder and ethanol as a liquid medium.

[0008] Another objective of the present invention is to provide a method for preparing sustained release tablets using a 3D printing process that utilizes semisolid extrusion and a layered double hydroxide (LDH)-based ink for producing tramadol hydrochloride-loaded tablets.

[0009] Yet another objective of the present invention is to provide a method for preparing tramadol hydrochloride-loaded Mg-Al-LDH, using sodium hydroxide, magnesium nitrate, aluminium nitrate and tramadol hydrochloride, to form a stable drug-intercalated layered double hydroxide structure for sustained drug release.

[0010] Another objective of the present invention is to provide a 3D printing method that ensures the sustained release of tramadol hydrochloride through the intercalation of the drug into Mg-Al-LDH, thereby enhancing the controlled release profile of the tablets.

[0011] Another objective of the present invention is to provide a method for preparing 3D-printed sustained release tablets that incorporates hydroxypropyl methylcellulose (HPMC) as a binder and ethanol as the sole solvent in the ink formulation to achieve a stable extrusion process.

[0012] Further objective of the present invention is to provide a method for preparing sustained release tablets that includes the application of a protective film coating using ethyl cellulose and polyethylene glycol polymers to further control drug release in varying pH conditions.



Summary of the invention:
[0013] The present disclosure sustained release tablets and a method for preparing the same using a 3D printing process, which utilizes layered double hydroxide (LDH)-based ink for producing tramadol hydrochloride-loaded tablets by semisolid extrusion.

[0014] The present invention provides a 3D-printed sustained release tablet formulation prepared by semisolid extrusion. The formulation includes tramadol hydrochloride-loaded Mg-Al-layered double hydroxide (Mg-Al-LDH), which serves as the drug delivery system. Hydroxypropyl methylcellulose (HPMC) is used as a binder and ethanol acts as the liquid medium to enable the 3D printing process. This formulation allows the production of sustained release tablets using 3D printing technology.

[0015] The tablets produced from this formulation exhibit sustained release of tramadol hydrochloride over a prolonged period, which improves the efficacy of drug delivery by maintaining a consistent drug release profile. This characteristic makes the formulation suitable for extended therapeutic effects and enhances patient compliance by reducing the frequency of dosage.

[0016] In a further aspect of the invention, the tablets may be coated with a protective film composed of ethyl cellulose and polyethylene glycol polymers. This coating serves to control the release of the drug in different pH conditions, particularly in acidic environments, thus preventing rapid degradation of the layered double hydroxide (LDH) structure.

[0017] For each tablet, the 3D printing ink used for semisolid extrusion is specifically formulated to contain 850 to 900 mg of tramadol hydrochloride-loaded Mg-Al-LDH, 40 to 45 mg of hydroxypropyl methylcellulose and 2 to 3 mL of 75% aqueous ethanol. This precise composition ensures the stability and consistency of the ink during the 3D printing process, resulting in uniform tablets with desired release properties.

[0018] The tramadol hydrochloride-loaded Mg-Al-LDH is prepared using 2.00 g of sodium hydroxide, 4.00 g of magnesium nitrate, 3.00 g of aluminium nitrate and 0.7391 g of tramadol hydrochloride. This process involves intercalating tramadol hydrochloride into the interlayer space of the Mg-Al LDH, forming a stable drug delivery system that enables sustained release.

[0019] The drug content in the dried tramadol hydrochloride-loaded Mg-Al-LDH is maintained at 11.0 to 12.0 weight percentage, ensuring adequate drug loading in the LDH structure while preserving the integrity of the LDH matrix.

[0020] The process for preparing the 3D-printed sustained release tablets includes several steps: intercalating tramadol hydrochloride into the Mg-Al LDH by mixing it with magnesium nitrate and aluminium nitrate solutions, followed by washing, vacuum drying and powdering; formulating a 3D printing ink by mixing the tramadol hydrochloride-loaded Mg-Al-LDH with hydroxypropyl methylcellulose and ethanol; printing the tablets using a semisolid extrusion technique in a 3D printer; and film coating the printed tablets with a coating solution made from ethyl cellulose, polyethylene glycol and dichloromethane.

[0021] Further, objects and advantages of the present invention will be apparent from a study of the following portion of the specification, the claims and the attached drawings.
Detailed description of drawings:
[0022] FIG. 1 illustrates a flowchart of a method for preparing the sustained release tablet formulation using a 3D printing process, which utilizes layered double hydroxide (LDH)-based ink for producing tramadol hydrochloride-loaded tablets by semisolid extrusion, in accordance to an exemplary embodiment of the invention.

[0023] FIG. 2 illustrates a Fourier-transform infrared (FTIR) spectrum of tramadol hydrochloride-loaded Mg-Al-layered double hydroxide (Mg-Al-LDH), in accordance to an exemplary embodiment of the invention.

[0024] FIG. 3 illustrates a powder X-ray diffraction (PXRD) pattern of tramadol hydrochloride-loaded Mg-Al-LDH, in accordance to an exemplary embodiment of the invention.

[0025] FIG. 4 illustrates a photograph of the 3D-printed sustained release tablet formulation utilizing layered double hydroxide (LDH)-based ink and semisolid extrusion, in accordance to an exemplary embodiment of the invention.

[0026] FIG. 5 illustrates dissolution profile of tramadol hydrochloride from the 3D-printed sustained release tablet formulation utilizing layered double hydroxide (LDH)-based ink, in accordance to an exemplary embodiment of the invention.


Detailed invention disclosure:
[0027] The present disclosure has been made with a view towards solving the problem with the prior art described above and it is an object of the present invention to disclose a 3D-printed sustained release tablet formulation utilizing layered double hydroxide (LDH)-based ink and a method of preparation thereof.

[0028] According to an exemplary embodiment of the invention, the invention discloses a specific ink composition optimized for the 3D printing process, composed of 850 to 900 mg of tramadol hydrochloride-loaded Mg-Al-LDH, 40 to 45 mg of hydroxypropyl methylcellulose and 2 to 3 mL of 75% aqueous ethanol. This composition ensures proper consistency for semisolid extrusion and uniform distribution of the drug within the tablet. The ink is prepared by thoroughly mixing the ingredients, ensuring homogeneity and stability throughout the 3D printing process.

[0029] According to another exemplary embodiment of the invention, the process of preparing tramadol hydrochloride-loaded Mg-Al-LDH involves the use of 2.00 g of sodium hydroxide, 4.00 g of magnesium nitrate, 3.00 g of aluminium nitrate and 0.7391 g of tramadol hydrochloride. This process creates a stable drug-intercalated layered double hydroxide structure that enables sustained drug release over time, with the intercalation process resulting in the controlled release of tramadol hydrochloride, providing extended therapeutic effects.
[0030] According to another exemplary embodiment of the invention, the final tramadol hydrochloride-loaded Mg-Al-LDH contains 11.0 to 12.0 weight percentage of tramadol hydrochloride, a concentration critical for achieving the desired sustained release profile and ensuring efficient drug loading into the LDH layers.

[0031] According to another exemplary embodiment of the invention, the present invention relates to a novel 3D-printed sustained release tablet formulation, specifically designed for the sustained release of tramadol hydrochloride. The tablet formulation is prepared using a semisolid extrusion 3D printing technique. The formulation consists of tramadol hydrochloride-loaded Mg-Al-layered double hydroxide (Mg-Al-LDH) as the primary drug carrier, hydroxypropyl methylcellulose (HPMC) as the binder and ethanol as the liquid medium.

[0032] According to another exemplary embodiment of the invention, the formulation exhibits sustained release of tramadol hydrochloride over a prolonged period. The layered double hydroxide (LDH) structure of Mg-Al-LDH allows for a gradual release of tramadol hydrochloride from the interlayers. This results in an extended therapeutic effect of the drug, improving patient compliance by reducing the frequency of administration.

[0033] The method for preparing the 3D-printed sustained release tablets involves several critical steps: first, tramadol hydrochloride is intercalated into the Mg-Al LDH by mixing it with magnesium nitrate and aluminium nitrate solutions, followed by washing, vacuum drying and powdering to create tramadol hydrochloride-loaded Mg-Al-LDH. Next, the drug-loaded Mg-Al-LDH is mixed with hydroxypropyl methylcellulose and ethanol to formulate a 3D printing ink suitable for semisolid extrusion. This ink is then loaded into a 3D printer head, which extrudes the ink through a nozzle to form tablets with precise control over dimensions and drug distribution. Finally, the printed tablets are coated with a protective film using a coating solution prepared using ethyl cellulose, polyethylene glycol and dichloromethane, applied to control drug release in varying pH conditions, particularly in acidic environments where the LDH structure may degrade.

[0034] According to another exemplary embodiment of the invention, FIG. 1 refers to a flowchart (100) of a method for preparing the sustained release tablet formulation using a 3D printing process, which utilizes layered double hydroxide (LDH)-based ink for producing tramadol hydrochloride-loaded tablets by semisolid extrusion. At step 102, intercalation of tramadol hydrochloride into the Mg-Al LDH is achieved by mixing tramadol hydrochloride with magnesium nitrate and aluminium nitrate solutions, followed by washing, vacuum drying and powdering. At step 104, the drug-loaded Mg-Al-LDH is mixed with hydroxypropyl methylcellulose and ethanol to create an ink that is suitable for 3D printing using semisolid extrusion. At step 106, 3D printing of the sustained release tablets is carried out by loading the ink into 3D printer head, which extrudes the ink through a nozzle to form the desired tablet shape. At step 108, the sustained release tablets obtained after 3D printing, are coated with a protective film using a coating solution made from ethyl cellulose, polyethylene glycol and dichloromethane.

[0035] According to another exemplary embodiment of the invention, FIG. 2 refers to a Fourier-transform infrared (FTIR) spectrum of tramadol hydrochloride-loaded Mg-Al-layered double hydroxide (Mg-Al-LDH); shows all the characteristics peaks of tramadol hydrochloride and Mg-Al-LDH.

[0036] According to another exemplary embodiment of the invention, FIG. 3 refers to powder X-ray diffraction (PXRD) pattern of tramadol hydrochloride-loaded Mg-Al-LDH. When tramadol hydrochloride is intercalated into the Mg-Al LDH interlayer, a sharp diffraction peak appears at a lower 2θ angle and the basal interlayer distance increases as the NO3⁻ anions are replaced by tramadol hydrochloride. This intercalation is further evidenced by the shift of planes to higher d-values. The basal spacing increases from 3.0426 Å to 3.8770 Å in the tramadol hydrochloride-intercalated LDH, confirming successful intercalation. The gallery space in the tramadol hydrochloride-intercalated Mg-Al LDH hybrid material was found to be 3.877 Å, larger than the original 3.0426 Å, verifying the incorporation of tramadol hydrochloride into the LDH interlayer.

[0037] According to another exemplary embodiment of the invention, FIG. 4 refers to a photograph of the 3D-printed sustained release tablet formulation utilizing layered double hydroxide (LDH)-based ink and semisolid extrusion.

[0038] According to another exemplary embodiment of the invention, FIG. 5 refers to dissolution profile of tramadol hydrochloride from the 3D-printed sustained release tablet formulation utilizing layered double hydroxide (LDH)-based ink. The in vitro dissolution study of 3D-printed sustained release tablets was performed in 0.1N HCl for the first 2 hours and in 6.8 pH phosphate buffer for the next 3 hours. Cumulative percent drug release (%CDR) was plotted against time in hours.

[0039] Numerous advantages of the present disclosure may be apparent from the discussion above. In accordance with the present disclosure a method for preparing sustained release tablets using a 3D printing process with layered double hydroxide (LDH)-based ink, is disclosed. The present disclosure provides novelty in producing sustained release tablets using 3D printing technology with a layered double hydroxide (LDH)-based ink. This specific ink formulation, composed of tramadol hydrochloride-loaded Mg-Al LDH, hydroxypropyl methylcellulose (HPMC) and ethanol, is tailored for semisolid extrusion in a single-head 3D printer. The intercalation of tramadol hydrochloride into Mg-Al LDH provides a unique drug delivery system that enables controlled and prolonged drug release.

[0040] The inventive step lies in the integration of 3D printing technology with the formulation of tramadol hydrochloride-loaded Mg-Al LDH for sustained release. The method combines the advantages of 3D printing (precision in tablet design and dosing) with the drug intercalation mechanism of Mg-Al LDH, resulting in a sustained release profile. This approach significantly improves upon traditional drug delivery systems by offering enhanced control over drug release rates and customized tablet shapes and dosing through 3D printing.

[0041] The present disclosure offers novelty in the realm of personalized medicine by combining 3D printing technology with a layered double hydroxide (LDH)-based ink for the production of sustained release tramadol hydrochloride tablets. The inventive step of this disclosure lies in the integration of 3D printing technology with LDH-based drug delivery systems to create a personalized sustained release formulation. This method allows for the tailoring of tablet size, drug concentration and release kinetics according to patient-specific needs, which is crucial in the field of personalized medicine. By using tramadol hydrochloride intercalated into Mg-Al LDH, the invention provides a sustained release mechanism that can be adjusted for individual patients, ensuring a prolonged therapeutic effect with fewer doses.

[0042] From the present disclosures, it may be apparent that the sustained release tablet formulation and method for preparing the same have significant industrial applicability in the pharmaceutical industry, particularly in the areas of personalized medicine, advanced drug delivery systems and 3D printing technology for tablet manufacturing. The invention's applicability extends across multiple facets of the pharmaceutical industry, from customized treatment regimes to high-precision manufacturing, thereby contributing to cost-effective, efficient and patient-specific medication production at an industrial scale.
, Claims:CLAIMS:
We Claim:
1. A 3D-printed sustained release tablet formulation of a highly water-soluble drug, prepared by semisolid extrusion, using:
tramadol hydrochloride-loaded Mg-Al-layered double hydroxide (Mg-Al-LDH);
hydroxypropyl methylcellulose as a binder; and
ethanol as a liquid medium.
2. The tablet formulation of claim 1, exhibiting sustained release of tramadol hydrochloride over a prolonged period.
3. The tablet formulation of claim 1, further comprising a protective film coating, wherein the coating is made of ethyl cellulose and polyethylene glycol polymers.
4. The tablet formulation of claim 1, wherein, for each tablet, the 3D printing ink used for semisolid extrusion comprises:
850 to 900 mg of tramadol hydrochloride-loaded Mg-Al-LDH;
40 to 45 mg of hydroxypropyl methylcellulose; and
2 to 3 mL of 75%v/v aqueous ethanol.
5. The tablet formulation of claim 1, wherein the tramadol hydrochloride-loaded Mg-Al-LDH is prepared using:
2.00 g of sodium hydroxide;
4.00 g of magnesium nitrate;
3.00 g of aluminium nitrate; and
0.7391 g of tramadol hydrochloride.
6. The tablet formulation of claim 1, wherein the drug content in the dried tramadol hydrochloride-loaded Mg-Al-LDH is 11.0 to12.0 weight percentage
7. A process for preparing a 3D-printed sustained release tablet formulation, comprising:
intercalating tramadol hydrochloride into the interlayer of Mg-Al layered double hydroxide by mixing tramadol hydrochloride with magnesium nitrate and aluminium nitrate solutions, followed by washing, vacuum drying and powdering;
formulating a 3D printing ink by mixing the tramadol hydrochloride-loaded Mg-Al-LDH with hydroxypropyl methylcellulose and ethanol;
printing the tablets using a semisolid extrusion technique in a 3D printer; and
film coating the 3D-printed tablets using a coating solution prepared with ethyl cellulose, polyethylene glycol and dichloromethane.
8. The process of claim 7, wherein , for each tablet, the 3D printing ink used in the formulation comprises:
850 to 900 mg of tramadol hydrochloride-loaded Mg-Al-LDH;
40 to 45 mg of hydroxypropyl methylcellulose; and
2 to 3 mL of 75%v/v aqueous ethanol.
9. The process of claim 7, wherein the tramadol hydrochloride-loaded Mg-Al-LDH is prepared using:
2.00 g of sodium hydroxide;
4.00 g of magnesium nitrate;
3.00 g of aluminium nitrate; and
0.7391 g of tramadol hydrochloride.
10. The process of claim 7, wherein the drug content in the dried tramadol hydrochloride-loaded Mg-Al-LDH is 11.0 to 12.0 weight percentage.

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