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Three-dimensional printing (3DP) is a layer-wise construction of 3D object based on a computer-designed model. This cutting-edge technology is extensively implemented in various areas, such as automotive, aerospace, bio-medical engineering and also pharmaceutical dosage forms manufacturing. Recently in December 2015, SPRITAM, the very first 3DP oral dosage form was approved by the U.S. Food and Drug Administration (FDA) and marketed for epileptic seizure treatment (Aprecia, 2015). This event indicates a significant breakthrough in pharmaceutical manufacturing and shows the pleasant prospect of 3DP within the pharmaceutical manufacturing industry. Due to its unprecedented versatility and accuracy, preparations of 3DP drugs are not limited to normal oral dosage forms, but also possible to be implemented in preparations for various routes of administration, such as implant system, suppositories, multiphase release tablets, rapidly disintegrating tablets and topical drug delivery system (Yu et. al., 2008). These dosage forms can come in unique geometry, complex internal structure which contains wide variety of materials, to meet the needs of specific therapy. Besides its high manufacturing efficiency, versatility and accuracy, its application in pharmaceutical industry also facilitates the development of customized medications and combinatorial therapy. Although having a bright future in replacing the traditional dosage forms, the 3DP technology might raise the issue of medication error and drug exploitation. Regulations and safety assessment should be addressed by agencies and standard organizations to ensure consumers’ safety.  

As compared to conventional dosage forms, 3DP drugs offer advantages in terms of ease of manufacturing. The manufacturing of conventional oral tablets involves a series of processes, including mixing, milling, granulation, coating etc., by using different machines in each of the steps. This multi-step manufacturing of the dosage forms has been afflicted by several challenges, including low batch-to-batch reproducibility, time consuming and drug degradation. On the contrary, 3DP of dosage forms involve only spreading of powder and depositing of binding solutions in layer-wise basis. Using a low cost 3D printer, the tablets can be printed in a single step (Yu et. al., 2008). Apart from minimal space and expenses requirement, the system can even be controlled remotely via computer network. By delaying the last step of dosage forms production, the drug manufacturing is brought closer to the patients (Alhnan, 2016). This is useful in overcoming the problem of drug degradation during storage, particularly 1,2,3-trinitroxypropane (nitroglycerin) used for angina pectoris treatment which is known to be unstable and degrades rapidly over time (Kommanaboyina & Rhodes, 1999). Eventually, 3DP permits the manufacturing of pharmaceutical dosage forms with a more effective way in terms of time, cost and space.

 

Being highly versatile, 3DP technology allows the use of diverse types of biocompatible printing materials for drug manufacturing, and thereby modifying drug release profile. Customarily, drug release is modified via enteric coating or incorporation of excipients which adjust the drug dissolution and disintegration rate to achieve the desired drug release profile. However, the use of these mechanisms is often limited by the conventional manufacturing method owing to the fact that only several materials are suitable to work with due to incompatibility and thermal sensitive issue during the conventional manufacturing. Fluctuations of dosage delivered might lead to unwanted side effect, overdosing and delayed treatment. 3DP technology can be employed on the fabrication of dosage forms with well controlled drug delivery system, such as topical delivery, sustained release, zero-order release multiphasic release.  

Current existing suppositories are cast using a base that melts at human temperature, enables the active pharmaceutical ingredients (API) to dissolve in biological fluids. The limitations is that these melted materials might leak out of human cavity and lead to ineffective therapeutic treatment.  The melting nature of these suppositories also makes it almost impossible to control the rate of drug release. It has been demonstrated that by using 3DP technology, a suppository incorporated within non-dissolving polymer is capable of achieving long-term analgesic effect suitable for conditions which oral forms of pain relievers are unable to result in the desired effect (Sun, 2016). Spritam, the first FDA-approved 3DP drug for epileptic seizure treatment, is designed with highly porous structure so that it disintegrates almost immediately within a sip of liquid (Aprecia, 2015). Besides being able to deliver large dose and lead to rapid onset of action, this drug also offers a more favorable alternative over the existing antiepileptic drugs for patients with swallowing difficulties, particularly the elderly and children. Combined with advance in manufacturing technology and material science, 3DP dosage forms can be fabricated with complex performance to achieve the desired curative effect.

Another strength offered by 3DP is the capability of handling diverse types of API including but not limited to poorly soluble drugs, biologically active drug molecules and drugs with low therapeutic index, which are difficult to be handled using conventional manufacturing. High degree of control over amount of materials loaded allows deposition of precise drugs dosage via 3DP. Studies have shown that it is possible for 3DP machine to load extremely low dosage precisely at micro to nanogram level with exceptional content uniformity (Kastra et. al., 2000). This offers novel strategies for incorporating API with narrow therapeutic window, which slight increment on drug dosage might lead to toxicity.

Furthermore, 3DP allows delivery of biologically active molecules, via oral and transdermal route. Biologically active molecules, especially proteins and peptides, has developed dramatically as therapeutic agents (Bruno, 2013). Due to low bioavailability and metabolic liability, these drugs can only be administered via intravenous or subcutaneous injection, yet there are still limitations on controlling release mechanism. 3DP Oral tablets designed with an outer barrier of enteric coating, protease-inhibitor containing region and protein drugs incorporated in the inner core are proposed to be competent at protecting the peptide drugs from enzymatic degradation within the gastrointestinal tract (Yu et. al., 2008; Bruno et. al., 2013). In another innovative way, peptide hormone can be delivered via transdermal microneedles array. Johnson (2016) and his team member has developed a versatile method of producing microneedles array within 10 minutes. These biodegradable microneedles coated or encapsulated with drug molecules are able to penetrate the skin and deliver drug molecules without stimulating nerve endings. Drug release rate can be managed by altering the amount of drug loaded and components of the microneedles over a desired period of time. This provides a remarkably less invasive alternative to injection of vaccine and hormones. Using these patches, self-administration by patients themselves is possible, especially for diabetic patients who require regular insulin treatment to maintain their blood glucose level (McAllister et. al., 2003). By dealing with the issue of drug safety, stability and delivery efficacy, 3DP technology contribute significantly to the pharmaceutical industry by enabling the incorporation of drugs, which are poorly delivered using the conventional method, in a much more controlled and effective way.  

In addition to controlling drug release, 3D fabricated dosage forms also allow the incorporation of multiple ingredients within one dosage forms. Multiple medications is another useful tactic in controlling complex chronic disease such as cancer and cardiovascular disease, which require the collaborating action of several active agents to relieve the symptoms. The patients are advised to take several drugs regularly at equal or different timings for optimal control of the disease state. Yet, the desired therapeutic effects are not always achieved due to pill burden that leads to medication errors and poor adherence of patients. 3DP technology is capable of handling complex geometry and highly accurate deposition of ingredients, either a single blend, multilayer with different APIs or multiple ingredients separated in different compartments. Drug loading and excipient composition in each compartment are manipulated to enable different drug release profile. The formulated ingredients are deposited precisely into the compartments, while the compartments are separated by suitable excipient to avoid incompatibility issues among API.

As demonstrated by Shaban (2015) and his research group, five components, pravastatin, atenolol, ramipril, aspirin, and hydrochlorothiazide, were incorporated into separate compartments in a single tablet. Aspirin and hydrochlorothiazide were mixed with disintegrants to achieve immediate release while pravastatin, atenolol and Ramipril were deposited together with a hydrophilic matrix within the sustained-release compartment.  The combination of five of these drugs commonly used for treatment of cardiovascular disease provides an acceptable and effective therapeutic regime for patients diagnosed with high risk of heart disease. This concept can be applied to treatment of other chronic disease, which combinatorial medications each with different drug delivery profile can be combined in a single tablet. With lowered pill burden, patients are more likely to adhere to the therapy. The ability of 3DP in combining multiple API within one dosage forms is likely able to reduce medication errors caused by patients, improve patients’ compliance and most importantly, enhance the therapeutic efficacy.

As mentioned, the advantages of 3DP technology include high versatility, effective production, precise spatial deposition and compatibility with diverse types of materials. These characteristics of the technology bring the world a step closer to personalized medications. The recommended doses of most currently available drugs and treatments are decided based on general populations, yet different responses and effects might be triggered among another subset of patients due to differences in disease state and physiological conditions. To illustrate, numerous currently evolved anticancer treatment are targeted at specific molecular level features of cancer cells yet the effect might vary from patients to patients due to heterogeneity of the disease. Tamoxifen, a highly effective drug prescribed for breast cancer, was discovered producing only limited effects in a subset of patients (Dezentjé, 2009). This drug is metabolized by cytochrome P450 2D6 (CYP2D6), which is polymorphically expressed in the human body. Patients with a limited number of CYP2D6 are unable to break down the drug molecules, causing the drug treatment to be ineffective.

To overcome these issues, customized medications, one of the futuristic strategies in pharmaceutical field, aims to design each formulation based on an individual’s profile of physiological and pathological conditions to ensure the optimal therapeutic outcome and lower risk of toxicity. This strategy requires the feasibility of producing a diverse types of dosage forms at a high production rate. As mentioned, the traditional dosage forms lack of flexibility and only suitable for large-scale manufacturing, unable to reach the demand of personalized medications. By using 3DP technology, personalized dosage forms can be designed with a wide range of structure and release mechanism within a short period of time.

   

In addition to oral dosage forms, 3DP has been demonstrated to be applied in fabrication of personalized topical drug delivery system. A nose-shaped mask containing salicylic acid was designed to resolve acne problem by using 3DP technology (Goyanes, 2016). This nose-shaped mask is specifically fabricated based on facial morphology of an individual to facilitate drug absorption. Moreover, the dosage form was formulated together with a hydrophilic base which greatly reduced the side effect caused by salicylic acid. Therefore, 3DP technology is potential in promoting personalized medications in such way that the patients are subjected to treatment with optimal effect based on individual disease state and physiological conditions.

Even though 3DP drugs provide compelling benefits over conventional dosage forms, there are several foreseen drawbacks of the technology, for instance, the medication error caused by lack of professional trainings and human error. Due to the highly adaptable properties of 3DP, dosage forms can be formulated in a wide variety of ways and even personalized for a specific subgroup of patients. Accordingly, the formulations and design of each dosage forms are decided independently. Besides training on the operation of 3D printing machines, personnel are required to be well-trained with in-depth understanding of physicochemical properties of each of the excipients and API as minimal discrepancies might impose significant impacts on the final product. Any adulteration and inaccurate dosing during the manufacturing will put the patients’ health at risk. There is a possibility that 3DP dosage forms might endanger patients’ health conditions due to improper formulations that stringent regulations over 3DP drugs are required. Specialised trainings related to formulation and prescription of 3DP drugs should be provided as lack of skilled professionals might impede the development of 3DP dosage forms.  

3DP is also possible to raise the risk of counterfeit and illegal drugs. With the advancement of 3DP technology, implementation of the technology within pharmaceutics manufacturing is becoming more and more available. Researchers are striving for making improvement on developing the machines so that the machines are more user-friendly in terms of size and user interface. As a consequence of reduced production cost and speed, it is also possible that the technology will be employed in manufacturing of illegal drugs. The misuser will have easier access to un-prescribed drugs, such as cocaine and opiates, consequently resulting in drug abuse. Meanwhile, counterfeit drugs will be more prevalently available in the market. These counterfeit drugs might not contain the right dose, ingredients, or be contaminated. Taking these drugs not only ineffective in alleviating the disease state, but also cause severe side effect on the patients’ health. Therefore, the usage of 3DP in dosage forms manufacturing has to be strictly governed in order to combat abusive usage of the technology in producing counterfeit and illegal drugs.

Seeing that 3DP drugs have the potential in replacing the conventional dosage forms, in-depth knowledge about the technology is still limited, issues of regulations and testing of 3DP drugs must be addressed to ensure patients\' safety before being widely implemented in the pharmaceutical industry. Due to the personalizable nature of 3DP dosage forms, regulation strategies might be necessary for each of the steps involved, including raw materials production and dosage form designing. Existing regulatory pathways of drugs are insufficient to assess 3DP drugs. International agencies and organizations, such as the United States Food and Drug Administration (FDA) and American Society for Testing and Materials (ASTM), has been proactively striving to provide standards, guidance and approaches to support modernization in the pharmaceutical industry. Current available resources are being leveraged with several considerations being taken into account to assess the quality, performance and safety of 3DP drugs.

The FDA has established the Emerging Technologies Team (ETT) within the Center for Drug Evaluation and Research (CDER), who is currently working with pharmaceutical companies to gain more insights on the science involved in 3DP drugs and medical devices (Markarian, 2016). Similar with conventional dosage forms, 3DP drugs are demanded to be manufactured in accordance to the existing chemistry, manufacturing and control (CMC) standards. A draft guidance on their initial recommendations on technical and manufacturing considerations for 3DP devices was published by the team in 2015, which serve to identify and resolve related issues (FDA, 2015). Meanwhile, the Committee F42 on Additive Manufacturing Technologies formed by ASTM are working on developing standards for 3DP technology in order to provide an overarching guidance on designing rules of 3DP. The committee has defined 7 categories for 3DP technologies and specified procedures for calibration of those printing machines (ASTM, 2012). Further improvement on these standards and guidelines are crucial to facilitate the designing and implications of 3DP technology in dosage forms manufacturing.

In essence, several advantages of 3DP dosage forms are highlighted in the literature, in terms of ease of manufacturing, controlling drug release and compatibility with diverse types of API. The procedures involved in manufacturing of 3DP drugs are much more efficient in time and cost as compared to conventional dosage forms. 3DP can be implemented in manufacturing of both traditional and innovative dosage forms, such as oral tablets, suppositories, implants, transdermal microneedles array etc., which each of them are fabricated with the desired drug release mechanism by manipulating several parameters. Besides its capability of handling diverse types of API, the technology also shows potential in facilitating the development of personalized medicine and combinatorial medications, which aim to enhance therapeutic efficiency, reduce side effect and improve patients’ compliance. Even though 3DP dosage forms are able to overcome limitations of the traditional dosage forms, understanding on the technology is still insufficient. It is foreseen that application of 3DP in dosage forms manufacturing might raise the problem of formulating error caused by lack of professional trainings and being exploited for production of counterfeit and illegal drugs. While researching extensively on the technology, agencies and standard organizations are working proactively in developing regulations and standards for 3DP dosage forms not only to encourage the development of 3DP drugs, but also protect the safety and rights of the patients at the same time.

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