As a Technical Entrepreneur, Do You want to Help the Society Fight against Infectious Diseases?
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The Optimum business Option is to Manufacture the Active Pharmaceutical Ingredient Molecules effective against Infectious Diseases.
Why?
Because when you talk about the medicines for Infectious Diseases, they&#;re effective because of the Active Pharmaceutical Ingredients. These powerful medications are formulated with these Active Pharmaceutical Ingredients. In fact, these active molecules actually fight with the Diseases.
If you talk about the active pharmaceutical ingredient molecules, they&#;re of two types:
Small Molecules
Active pharmaceutical ingredients coming under the small molecule category are low molecular weight compounds. If you study the active pharmaceutical ingredients used in the medications, you&#;ll find the major percentage to be small molecules.
Large Molecules
Active pharmaceutical ingredients coming under the large molecule category are structurally very complex and have high molecular weights. In fact, most of these molecules are protein based. The industrial manufacturing involves biotechnological processes.
However, we shall focus on Small Molecules in this article.
Before getting into the details of the active pharmaceutical ingredient molecules, it&#;s necessary to know about the infectious diseases.
Infectious Diseases
The cause of getting affected with infectious disease is infection. We get infected when disease causing pathogens invade our body. These disease-causing pathogens, are in fact microorganisms. They&#;re very small and you can&#;t see them in the naked eye. You&#;ll need a microscope to see them.
These pathogenic microorganisms are of different types:
- Pathogenic Bacteria : When you get infected with pathogenic bacteria, you get bacterial diseases.
- Fungal Pathogens : When you get infected with fungal pathogens, you get fungal diseases.
- Disease Causing Virus : When you get infected with disease causing virus, you get viral diseases.
- Disease Causing Parasite : When you get infected with disease causing parasite, you get parasitic diseases.
Though the medicines for infectious diseases are essential for all of us, they must be manufactured at large scale in sufficient quantities at reasonable costs. Why?
Because unless they&#;re available at affordable prices all of us can&#;t take the advantage of them and it won&#;t serve any useful purpose.
But in order to make the medicines for infectious diseases available at affordable prices, you need to manufacture high quality active pharmaceutical ingredient molecules at low costs. Why?
Because, as I&#;ve mentioned before active pharmaceutical ingredients make the medicines effective. And so, the availability and the cost of the medicines for infectious diseases, will depend on the availability and the cost of the concerned active pharmaceutical ingredients.
But as a Technical Entrepreneur, manufacturing of active pharmaceutical ingredients must make business sense. Right?
Apart form many aspects, the two things which can make the difference between success and failure of any business are:
- Market Demand
- Profitability
Let&#;s first get into the details of the market demand&#;
The Market Demand is going up
The market for active pharmaceutical ingredients especially for infectious diseases, is growing very fast due to multiple reasons:
- Many infectious diseases are very dangerous and life threatening. In that situation, you must start medical treatment as early as possible.
- Today, because of increased health awareness, medicine consumption is increasing rapidly.
- Because of the increased income levels, more and more people can afford quality medicines. And they&#;re reluctant to ignore the diseases especially the infectious diseases because of their seriousness. It has resulted in increased medicine consumption.
- Because of massive improvements in manufacturing technologies coupled with wide spread entrepreneurial mindset, the manufacturing costs have come down. As a result, medicines for infectious diseases are available at affordable prices.
Now, it&#;s time to talk about the profitability.
The Profitability is More
There&#;s significant increase in the profitability of manufacturing active pharmaceutical ingredient molecules especially for infectious diseases. You can achieve exponential sustainable business growth because of the possibility of backward and forward integration.
The profitability is more because of multiple factors like:
- More and more active pharmaceutical ingredient molecules for infectious diseases are getting added to the list of products to manufacture.
- Advanced technologies have made it easy to make the complex molecules at low manufacturing costs.
- When you manufacture the active pharmaceutical ingredient molecules from the basic stage, the value addition is more. That&#;s how you can manufacture high priced products from low-cost raw materials.
- With active pharmaceutical ingredient manufacturing the sales turnover to investment is high. And the result is reduction in the financial cost and increase in the profit margin.
- With active pharmaceutical ingredients manufacturing, demand supply gap is significant. In fact, the supply doesn&#;t match the demand for many molecules. It has resulted in the increase in the selling prices.
As we&#;ve already discussed about the market demand and the profitability, let&#;s talk about the active pharmaceutical ingredient molecules.
If you study the medicine market closely, you&#;ll find hundreds of profitable active pharmaceutical ingredient molecules for infectious diseases are used in pharmaceutical formulations.
Before proceeding further, let&#;s see how the active pharmaceutical ingredient molecules are manufactured.
Manufacturing Processes
When you analyze the manufacturing processes of active pharmaceutical ingredient molecules for infectious diseases, you&#;ll find four different types:
- Chemical Synthesis
- Fermentation Process
- Enzymatic Reaction
- Extraction from Natural Sources
But most of the manufacturing processes of active pharmaceutical ingredient molecules, involve chemical synthesis. And it&#;s difficult to synthesize them because of the complexity of the reaction mechanisms and multiple reaction steps.
So, it becomes necessary to make the manufacturing process easy involving less number of synthesis steps. But how to do it?
Pharmaceutical Intermediates
And here the availability of pharmaceutical intermediates makes the difference. Multiple pharmaceutical Intermediates are required to manufacture a single active pharmaceutical ingredient. But as a manufacturer, you start with pharmaceutical intermediates and your manufacturing processes become short and easy.
So, you&#;ve got the option to either make the active pharmaceutical ingredient molecules from the basic stage or using the available pharmaceutical intermediates. Both the options have their own plus and minus points depending on the business need and the market situation.
Now coming back to the product selection.
Product Selection
How to select the right active pharmaceutical ingredient molecules for infectious diseases to manufacture?
Looking to the competitive business environment, you must do detailed analysis of the technical and economic aspects in order to select the right product. This becomes more important because of the knowledge intensive nature of the active pharmaceutical ingredients manufacturing business.
We&#;ve covered more than 101 active pharmaceutical ingredient molecules for infectious diseases, in order to introduce you to their usage in pharmaceutical industry. So that you can know more about them based on your interests and requirements.
But if you study the list, you can observe that many molecules are not mentioned in the list.
In fact, any of them can be suitable for your business. So, what you need to do is to explore the possibilities and learn as much as you can about these products and their usage in pharmaceutical industry.
Let&#;s get in to the list of 101 active pharmaceutical ingredient molecules for infectious diseases you can manufacture in your manufacturing facility and make your business profitable and sustainable.
As you&#;re aware, different infectious diseases need different medications. And different active pharmaceutical ingredients are necessary for different medications.
That&#;s why I&#;ve listed the active pharmaceutical ingredient molecules for infectious diseases, under different medication categories. It&#;ll help you to have a feel of their usage in pharmaceutical industry.
Though many molecules perform similar functions, their molecular structures are different. That&#;s why you can classify the molecules for making the medications for infectious diseases in many ways. The idea is to introduce you to the commercially important molecules.
Beta Lactam Antibiotics
Beta Lactam Antibiotic molecules are very effective in treating bacterial infections. They work by killing the pathogens by inhibiting cell wall formation. The molecules can be based on Penicillin, Cephalosporin or Carbapenem functional groups.
Some of the commercially important molecules you can evaluate for manufacturing are:
Penicillins
1. Amoxicillin
2. Ampicillin
3. Cloxacillin
4. Oxacillin
5. Flucloxacillin
Cephalosporins
6. Cephalexin
7. Cefadroxil
8. Cefazolin
9. Cefaclor
10. Ceftazidime
11. Cefuroxime
12. Cefotaxime
13. Ceftriaxone
14. Cefixime
15. Cefpodoxime
16. Cefprozil
17. Cefdinir
18. Cefepime
19. Cefditoren
Carbapenems
20. Imipenem
21. Meropenem
22. Ertapenem
23. Doripenem
Macrolide Antibiotics
Macrolide Antibiotic molecules are very effective in treating bacterial infections. They work by killing the pathogens by inhibiting their protein biosynthesis.
Some of the commercially important molecules you can evaluate for manufacturing are:
24. Erythromycin
25. Roxithromycin
26. Azithromycin,
27. Clarithromycin
Quinolone Antibiotics
Quinolone Antibiotic molecules are very effective in treating bacterial infections. They work by killing the pathogens by inhibiting their DNA replication.
Some of the commercially important molecules you can evaluate for manufacturing are:
28. Ciprofloxacin
29. Levofloxacin,
30. Norfloxacin
31. Moxifloxacin
32. Ofloxacin
Other Antibiotics
There are many other Antibiotic molecules for treating bacterial infections. They work in many ways to kill the bacterial pathogens and cure you from infectious diseases.
Some of the commercially important molecules you can evaluate for manufacturing are:
33. Tetracycline
34. Doxycycline
35. Clindamycin
36. Lincomycin
37. Vancomycin
38. Gentamycin
39. Amikacin
40. Neomycin
41. Sulfamethoxazole
42. Trimethoprim
43. Linezolid
Antifungal Molecules
Antifungal molecules are very effective in treating fungal infections. They work by killing the fungal pathogens by damaging their cell membranes.
Some of the commercially important molecules you can evaluate for manufacturing are:
44. Amphotericin B
45. Griseofulvin
46. Caspofungin
47. Ketoconazole,
48. Clotrimazole,
49. Miconazole
50. Fluconazole,
51. Itraconazole,
52. Tioconazole
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53. Posaconazole,
54. Voriconazole
55. Luliconazole
56. Sertaconazole
57. Terbinafine.
58. Butenafine
Antiparasitic Molecules
Antiparasitic molecules Quinolone Antibiotic molecules are very effective against the parasites. They work by killing them or inhibiting their growth.
Some of the commercially important molecules you can evaluate for manufacturing are:
59. Amodiaquine
60. Artemether
61. Artesunate
62. Mefloquine
63. Chloroquine
64. Ivermectin
65. Metronidazole
66. Ornidazole
67. Tinidazole
68. Mebendazole
69. Albendazole
70. Thiabendazole
71. Triclabendazole
72. Nitazoxanide
73. Niclosamide
74. Proguanil
75. Atovaquone
76. Praziquantel
Antiviral Molecules
Antiviral molecules are very effective in treating viral infections. They work against viral pathogens by inhibiting viral replication.
Some of the commercially important molecules you can evaluate for manufacturing are:
77. Abacavir
78. Atazanavir
79. Acyclovir
80. Ganciclovir
81. Valganciclovir
82. Valaciclovir
83. Tenofovir
84. Ritonavir
85. Lopinavir
86. Darunavir
87. Dolutegravir
88. Raltegravir
89. Oseltamivir
90. Saquinavir
91. Favipiravir
92. Efavirenz
93. Cobicistat
94. Rilpivirine
95. Zidovudine
96. Lamivudine
97. Emtricitabine
98. Entecavir
99. Abacavir
100. Indinavir
101. Nelfinavir
102. Remdesivir
103. Nevirapine
104. Famciclovir
105. Sofosbuvir
106. Fosamprenavir
107. Didanosine
Hundreds of active pharmaceutical ingredients are used in making thousands of medications for infectious diseases. New molecules are getting added to the list very fast and are improving the medical treatment.
Some molecules have very good market, whereas some have limited market and used for difficult to treat diseases. Some are easy to manufacture, while for some the manufacturing process is complex. The techno-commercial aspects vary from product to product.
So, it&#;s very difficult to keep track. But as a technical entrepreneur, you must learn as much as possible about the business aspects of manufacturing active pharmaceutical ingredients meant for treating infectious diseases.
Let&#;s Conclude
As we&#;ve mentioned earlier, the best way to get associated with High Potential Fast Growing Pharmaceutical Industry is manufacturing active pharmaceutical ingredients used in the medications for treating infectious diseases. Why?
Because it&#;ll help you not only to achieve Business Success but also to Contribute to the Society significantly. The modern world can&#;t sustain without Medications.
So, as a Technical Entrepreneur you can make the medicines for infectious diseases available to all at affordable prices, by manufacturing high quality active pharmaceutical ingredient molecules at low costs.
As we&#;ve discussed earlier, the most important but difficult business function is Product Selection. But the best part is, there&#;re many commercially important active pharmaceutical ingredients for infectious diseases you can manufacture in your manufacturing facility profitably and sustainably.
Here, we&#;ve covered more than 101 active pharmaceutical ingredients molecules for infectious diseases, in order to introduce you to the world of commercially important pharmaceutical industry products.
But when you study the products and evaluate them in a targeted way against important techno-commercial basis, you&#;ll come to know about the opportunities and constraints of active pharmaceutical ingredients manufacturing.
And it&#;s just the beginning. When you look at them from a technical entrepreneur&#;s eye, you can appreciate the possibilities and make efforts to know more about them. Of course, you&#;ll consider the products based on your interests and requirements.
As we&#;ve mentioned earlier, the business environment is changing very fast. The raw materials which are available today, may not be available tomorrow. The existing products may become obsolete and new products may take their places.
Things are also moving fast in the technology front. Advanced technologies are getting developed to address the industrial issues and make the manufacturing processes profitable and sustainable.
But the most important part is to make use of the information. Why?
Because you need to optimize the diverse techno-commercial aspects, in order to utilize the incredible opportunities, the active pharmaceutical ingredients manufacturing business offers.
When you identify the techno-commercial gaps and give your own inputs, you can develop great profit-making manufacturing ideas and add tremendous value.
But it calls for industrial experience and techno-economic expertise. Perhaps you can consider taking the help of Industry Experts to make the process fast and effective.
How will You Select the Active Pharmaceutical Ingredients used for Treating Infectious Diseases to Manufacture?
For the last 40 years, praziquantel has been the standard treatment for schistosomiasis, a neglected parasitic disease affecting more than 250 million people worldwide. However, there is no suitable paediatric formulation on the market, leading to off-label use and the splitting of commercial tablets for adults. In this study, we use a recently available technology, direct powder extrusion (DPE) three-dimensional printing (3DP), to prepare paediatric Printlets&#; (3D printed tablets) of amorphous solid dispersions of praziquantel with Kollidon ® VA 64 and surfactants (Span&#; 20 or Kolliphor ® SLS). Printlets were successfully printed from both pellets and powders obtained from extrudates by hot melt extrusion (HME). In vitro dissolution studies showed a greater than four-fold increase in praziquantel release, due to the formation of amorphous solid dispersions. In vitro palatability data indicated that the printlets were in the range of praziquantel tolerability, highlighting the taste masking capabilities of this technology without the need for additional taste masking excipients. This work has demonstrated the possibility of 3D printing tablets using pellets or powder forms obtained by HME, avoiding the use of filaments in fused deposition modelling 3DP. Moreover, the main formulation hurdles of praziquantel, such as low drug solubility, inadequate taste, and high and variable dose requirements, can be overcome using this technology.
The aim of this study was to use an innovative technology, DPE 3DP, to overcome the main challenges of formulating PZQ for paediatric patients: low drug solubility, unacceptable taste, and requirement for a range of relatively high drug doses, by preparing PZQ ASDs as paediatric Printlets&#; (3D printed tablets). The suitability of different powdered materials to directly feed the 3D printer was investigated. The powdered materials tested were physical mixtures of crystalline drug and polymer, and for the first time, pellets and powder forms obtained from ASD&#;HME extrudates. The characteristics of the resulting printlets were evaluated, with special focus on drug dissolution profiles, taste masking effectiveness, and physical stability.
One of the technical limitations of the FDM 3DP process is the high dependency on the physical and mechanical properties of the filaments for printing feasibility [ 26 , 43 ], and the difficulty of filament preparation [ 44 ], especially when high drug loads are required. Recently, direct powder extrusion (DPE), a new 3DP technology that does not require the preparation of filaments using HME and allows the direct extrusion of drug and excipient mixtures in the powder form, was reported [ 26 , 45 ]. This technique has allowed the production of 35 wt% itraconazole tablets via a single step process, with improved solubility characteristics through itraconazole amorphisation during printing [ 26 ].
ASDs can be prepared using different technologies, one being hot melt extrusion (HME), a process in which a material is melted or softened under an elevated temperature and pressure, and is forced through a die by rotating screws [ 24 ]. HME has been recently used to obtain filaments for the preparation of personalised medicines using three-dimensional (3D) printing [ 25 ]. Three-dimensional printing (3DP) is an innovative additive manufacturing technique, capable of converting 3D computer models into real objects by the sequential deposition of material in a layer by layer manner [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. Currently, the most evaluated 3DP technique in the pharmaceutical area is fused deposition modelling (FDM), as a result of the low printer cost, the good quality of the final product, and the direct use of filaments obtained by HME [ 37 ]. Many HME&#;FDM studies have shown the potential opportunities of preparing medicines with different drugs [ 38 ], designs [ 39 ], and release profiles [ 35 , 40 , 41 ], even for paediatric formulations [ 42 ].
Various approaches have been evaluated to overcome the aforementioned obstacles, one being the transformation of the drug solid state structure from crystalline to amorphous [ 15 , 16 , 17 , 18 ]. The use of an amorphous form of the drug requires its physical stabilisation in the formulation, which can be achieved by the formation of amorphous solid dispersions (ASDs). The principle of an ASD is based on the dispersion of drug in an amorphous carrier, generally a polymer, generating a homogeneous mixture of reduced molecular mobility [ 19 ]. In addition to solubility enhancement properties, the dispersion of the drug within the polymer matrix could be expected to contribute towards taste masking. Solid dispersions of paracetamol and Eudragit ® E have already been studied and demonstrated successful taste masking of the drug [ 20 , 21 ]. The combination of both properties (solubility improvement and taste masking) is an important requirement for paediatric patients. This patient group presents a great diversity in terms of anatomy and physiological and psychological responses when compared to adults, and as a result, varied therapeutic responses. Although the palatability of a drug is not the only factor that affects the acceptance of a drug, for unpalatable drugs, it is commonly listed as the first cause of non-adherence to treatment, especially in children [ 13 , 22 , 23 ].
The development of a suitable PZQ formulation for children is challenging since: (a) it exhibits a low water solubility (0.02 mg/mL&#;class II of the Biopharmaceutics Classification System (BCS)) [ 14 ], (b) a variable dose dependent on the patient&#;s weight is needed to achieve a standard 40 mg/kg dose to treat preschool-aged children [ 3 ], and (c) it requires the use of an effective taste masking technology.
The current treatment for children is based on the off-label use of PZQ, and the dose adjustment is carried out by splitting commercial tablets for adults [ 3 , 4 , 12 ]. However, such an approach is dangerous, as dosing errors lead to potential toxic side effects or lack of treatment effect [ 9 ]. In conjunction, PZQ has an unpleasant taste and the splitting of tablets favours taste bud exposure to the bitter drug, leading to the rejection of the medication and, consequently, to therapeutic ineffectiveness [ 9 ]. Palatability is a determining factor in dosage form acceptability and patient adherence to treatment, especially for paediatric oral formulations [ 13 ].
Praziquantel (PZQ) has been the standard treatment for over 40 years, and is included on the WHO Model List of Essential Drugs [ 9 , 10 ]. It is also used in preventive chemotherapy due to its efficiency, low cost, and promising safety results [ 10 , 11 ]. Although school-aged children have been the primary target to treat the disease, together with toddlers and children under six years of age, there is currently no suitable formulation available for paediatric patients on the market [ 3 , 4 ].
Schistosomiasis is considered one of the most prominent neglected diseases in public health, affecting around 250 million people in more than 70 countries worldwide [ 1 , 2 , 3 , 4 ]. Even more alarming is the number of school-aged children (5&#;14 years old) requiring treatment, which has been estimated to be around 25 million [ 2 , 5 , 6 ]. The disorder, caused by parasitic worms, is responsible for the highest morbidity and mortality rates in developing countries [ 7 ]. To this day, approximately 90% of cases are found in Africa and South America, specifically Brazil, reaching 8&#;10 million cases of Schistosoma mansoni [ 2 , 7 , 8 ].
The samples were stored in a Memmert HPP260eco climatic chamber (Memmert, Schwabach, Germany) at 25 °C and 60% relative humidity (RH) for a period of 3 months. The printlets were packaged in amber glass bottles, while the printed discs were stored in transparent glass bottles protected by aluminium. All bottles were closed with plastic screw caps. They were monitored by DSC (printlets) and XRPD (discs) analysis over the period of storage.
The PZQ taste-concentration profile was previously determined with the rat brief-access taste aversion (BATA) model [ 48 ]. It was found that the half maximal inhibitory concentration (IC50) was 0.06 mg/mL, and the taste threshold was 0.03 mg/mL. The classification proposed by Mohamed-Ahmed et al. [ 48 ] was used to classify levels of PZQ released at different time points as fully tolerated, well tolerated, tolerated, aversive/untolerated, or highly aversive/highly untolerated, and predict taste masking efficiency of the different formulations.
The simulated salivary fluid (SSF) (Sodium chloride&#;8 g/L; Potassium phosphate monobasic&#;0.19 g/L; Sodium phosphate dibasic&#;2.38 g/L; pH 7.4) [ 47 ] kept under magnetic stirring at 37 °C ± 1 °C, was pumped through the &#;buccal dissolution column&#; using a peristaltic pump at a rate of 1 mL/min, corresponding to an average adult normal total simulated saliva flow range. The other two adjacent parts were composed of wire mesh discs, placed either side of the column. After inserting the sample in the centre of the column lumen, from the top, aliquots were collected at 60, 120, 180, 240, 300, 360, 420, 480, 540, and 600 s, filtered through a 0.22 um membrane, and PZQ analysed by HPLC. Tests were conducted in triplicate. Data are reported throughout as mean ± standard deviation using Microsoft Excel (Microsoft Corp., Redmond, WA, USA) software (version MSO).
The in vitro method described by Keeley et al. [ 46 ] was used to predict the taste of PZQ released from the milled extrudates and printlets in a simulated buccal environment.
The drug release profiles of the printlets were monitored using a USP-II paddle apparatus (DT 60) (ERWEKA, Heusenstamm, Germany). Paddle stirrers at a speed of 50 rpm and temperature of 37 ± 0.5 °C were used in each test. The printlets were placed at the bottom of a 900 mL vessel of 0.1M HCl media (without surfactant). During the dissolution test, 5 mL samples were taken and filtered through 0.22 µm PTFE filters, and the drug concentration was determined by HPLC (method described in Section 2.2.3 (Determination of Drug Loading)). Tests were conducted in triplicate. Data are reported throughout as mean ± standard deviation.
The validated HPLC assay involved the injection of 10 µL samples through a Protosil C18 column at room temperature (25 °C) (150 × 4.60 mm&#;5 µm) (Phenomenex, Bologna, Italy) in an isocratic mode with mobile phase consisting of methanol and water (60:40 v/v) at a flow rate of 1.5 mL/min. A wavelength of 210 nm was used for detection. The retention time of PZQ was found to be approximately 3 min and the run time was set at 10 min.
One printlet of each formulation was placed in a volumetric flask with 60:40 acetonitrile: water mixture (50 mL) under ultrasound for 5 min until complete dissolution (n = 2). Samples of the solutions were then filtered through a 0.22 μm PTFE filter (Millipore Ltd., Dublin, Ireland) and the concentration of drug was determined by external standardisation. Quantification was carried out using a fresh standard stock solution prepared each time before starting the analysis. The standard solution of PZQ was prepared by dissolving 9 mg of PZQ in mobile phase to obtain a final concentration of 0.18 mg/mL. Each sample solution was prepared and analysed in duplicate. The results were expressed as a % of PZQ recovery.
Raman mapping was performed at room temperature (25 °C) using a Raman 300R Alpha confocal microscope (WITec GmbH, Ulm, Germany), equipped with a laser at a wavelength of 532 nm. Samples were analysed by a 50× objective on the surface and deep mapping (8 × 8 μm KOL, 5 × 5 μm PZQ, and 10 × 10 μm and 10 × 20 μm P and M printlets, respectively) was applied to predict drug and polymer distributions.
The analysis was performed using a DSC Q200 with the base module and modulated DSC (mDSC) (TA instruments, New Castle, DE, USA). An RCS90 cooling system was used to precisely control the cooling rate. Nitrogen (N 2 ) was used as the purging gas at 50 mL/min, and the analysis was carried out in non-hermetic aluminium pans. Indium standards were used for enthalpy and temperature calibration, and an empty aluminium pan was used as a blank control. As for mDSC, sapphire was used to calibrate the instrument for specific heat capacity (Cp) measurements. Samples were heated at a rate of 2 °C/min from 10 to 180 °C, with a modulation period of 40 s and an amplitude of 0.2 °C. Two samples of each printlet (average weight of each sample: 2&#;6 mg) were analysed: one taken from the border and the other taken from the core.
Discs of 20 mm diameter × 2 mm height from the same printlet formulations were 3D printed and analysed. A Philips X&#;Pert Panalytical X-ray diffractometer (Malvern Panalytical, Malvern, UK) using CuKα radiation, 40 mA of current, and 45 kV of voltage was used. The recording spectral range was set at 7&#;50° with a measuring step (angular deviation between 2 consecutive points) of 0.° and an acquisition time of 100 s per point. In addition, each disc was rotated in its sample holder (1 revolution/s) during the results acquisition. Disc printing was performed only for feeding with HME-extrudate powder. X-ray powder diffraction (XRPD) analysis was performed for the ground raw and extruded materials using the same method.
Images were obtained using a Leica EZ4 HD ® microscope (Leica, Wetzlar, Germany) with an integrated high-definition digital camera, set to 8× magnification. The images were then edited with the Leica LAS EZ software program. For calibration purposes, an image (obtained under the same conditions) of a standard slide containing a straight 1 cm segment, with 100 divisions, was employed.
After printing each formulation, the extruder was removed from the printing platform and the screw and barrel were dismounted and washed to avoid cross-contamination between different formulations.
The 3D printer used (FabRx Ltd., Kent, UK) was specifically designed with a direct single-screw powder extruder and a nozzle diameter of 0.8 mm. Its design is based on a single-screw HME with rotation speed (and hence extrusion) controlled by the 3D printer software (Repetier-Host V 2.1.3, Willich, Germany). Furthermore, the extruder nozzle moves in three dimensions to create the objects in a layer-by-layer fashion ( ).
The prepared mixtures, pellets or milled extrudates, were then added to the hopper of a M3DIMAKER&#; pharmaceutical 3D printer (FabRx Ltd., London, UK) with a direct powder extruder nozzle as previously reported [ 26 ]. AutoCAD (Autodesk Inc., San Rafael, CA, USA) was used to design the templates of the printlets, which were then exported as a stereolithography (.stl) file into the 3D printer software (Repetier host V 2.1.3, Willich, Germany). The selected 3D geometry was a cylindrical printlet (10 mm diameter × 3.6 mm height). The printer settings in the Repetier Host software were as follows: feed steps/mm, infill 100%, high resolution with brim, without raft, speed while extruding (20 mm/s), speed while travelling (90 mm/s), number of shells (2), and layer height (0.20 mm). The flow rate, extruder temperature, and feed rate were adjusted for each formulation ( ).
The three formulations of PZQ processed by HME contained 35 or 50 wt% PZQ, in the presence/absence of surfactants. The addition of the surfactants (Span or SLS) in the formulations was to increase the dissolution of the solid dispersions produced by HME. This investigation was conducted for the formulation containing 35 wt% of PZQ. The surfactant Span (liquid) was added using a peristaltic pump (Thermo Scientific&#;, Dreieich, Germany) directly into the extruder, while the surfactant SLS (solid) was directly added to the PZQ and polymer during physical mixture preparation. The respective placebo formulations were produced (M Placebo Span and M Placebo SLS) to check the printer&#;s cleanliness by contaminating the batches with PZQ prior to printing.
The physical mixtures (PM 50, PM 35, and PM 35 SLS) were prepared in a Turbula ® T2F mixer (96 rpm, 8 min). HME extrudates were prepared using a Thermo-Fisher pharma 16 Extruder (Thermo scientific&#;, Karlsruhe, Germany), in a co-rotating twin-screw configuration with eight heating zones, two mixing zones, and a screw diameter (D) of 16 mm and L/D ratio equal to 40 (L being the length of the barrel). The heating zones of the extrusion were determined for each of the formulations according to their specific characteristics, ranging from 50 to 180 °C. The HME extrudates were cut into pellets of 1 mm in length. Part of the binary formulation was used as pellets (P 50), and part was milled (M 50). The two ternary formulations (M 35 Span, M 35 SLS) were milled. The milling process was carried out using a Quadro Comil H5 High Energy Mill (Fitzpatrick ® , Waterloo, ON, Canada) with a mill speed of rpm and a 610 µm size sieve. The samples were protected from light and kept in a desiccator for conservation.
Racemic praziquantel (MW 312.4 g/mol) (PZQ) was kindly provided by Farmanginhos/Fiocruz from Brazil. Kollidon ® VA 64 (MW 45,000&#;70,000 g/mol) (KOL) and Kolliphor ® SLS Fine (SLS) were donated by BASF Chemical Company, Ludwigshafen, Germany, and Span&#; 20 (Span) by Croda International, Snaith, UK. Acetonitrile HPLC/Spectro and Methyl Alcohol HPLC/Spectro came from Tedia Company, Fairfield, USA. For the analysis, distilled and purified water (conductivity of 18.2 MΩ.cm at 23 °C) was obtained by the purification system Milli-Q (classic Purelab DI, MK2) (Elga, High Wycombe, UK). Sodium chloride and potassium phosphate monobasic were obtained from Merck (Darmstadt, Germany), praziquantel reference standard was purchased from USP (Rockville, MD, USA) and sodium phosphate dibasic from Sigma-Aldrich (St. Louis, MO, USA).
3. Results
3.1. Physical Printlet Characteristics
PZQ printlets with different compositions were investigated in the present work to find the best solution for a PZQ formulation to treat schistosomiasis in children. The work was designed to obtain PZQ printlets and to demonstrate the feasibility of producing medications with personalised doses in printlets of 10 mm diameter and 3.6 mm height. The pictures of the best formulations are shown in .
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The physical mixture of PZQ and KOL (PM 50) was directly added to the hopper of the 3D printer extruder, but the feeding material hampered the printing process and led to unsatisfactory final products (pictures not shown). Varying mass feed rates and screw speed parameters were tested, but none produced printlets with a satisfactory visual quality or enough extruded material. The poor flow of the mixture and electrostatic forces caused high variation in the feeding during printing, making it impossible to produce a continuous and homogeneous flow of material through the screw.
A similar and unsatisfactory behaviour was verified when another physical mixture of PZQ (PM 35 SLS) was directly added to the hopper of the 3D printer extruder. These results showed that, for 3DP with direct powdered material feeding, powder characteristics capable of providing fluidity and homogeneity are essential to a regular flow through the extruder [49]. Without adding additional excipients to improve the flow properties of physical mixtures, it was not possible to obtain good quality printlets from both PZQ formulations.
For the third tested formulation (PM 35 Span), printing was not possible since the mixture could not be prepared with the same conditions used for HME extrusion (addition of the liquid surfactant directly into the extruder).
Alternative processed materials were directly fed into the 3D printer: pellets obtained by HME, and powders obtained from the milled pellets. The main objective of printing using pellets was to facilitate the overall process and overcome the need for milling. Although it was possible to print with pellets, the flow into the printer was inconsistent, most likely due to the size (~1 mm) and the lack of homogeneity in the materials&#; particulate morphology. The printing of the printlets using the sample P 50 was possible, however, for a limited number of printlets, since the cleaning of the screw was necessary after each unit produced. For this reason, only DSC analysis was performed for this sample to verify the thermal behaviour after printing and during the stability testing period.
In contrast, milled materials provided a continuous flow, and the printing process was notably improved. However, it was evidenced that the feed rate was impacted by the drug load in the system. The samples in the milled form with a load of 35 wt% PZQ (M 35) showed greater ease of continuous printing compared to the sample containing 50 wt% PZQ (M 50). As a result, even the M 50 formulation presented limitations in the printlet reproducibility. Due to this, SEM and palatability analyses were not performed. Even with these limitations, the characterisations present in this work are an important step as they demonstrate the possibility of printing with high drug load materials obtained by HME.
The images obtained by optical microscopy of PZQ printlets are shown in . The variation in printlet colour is related to the differing composition of each one. After the HME process, both tested formulations containing surfactant (M 35 Span and M 35 SLS) had a yellow appearance, with the most intense coloration for the one containing SLS. This is most likely because the surfactant interacts with other formulation components (polymer and drug), resulting in a colour change. This feature was constant for the respective printlets produced with the M 35 Span and M 35 SLS formulations. Interactions (chemical and/or physical) between API and excipients can affect characteristics such as stability, chemical nature, and bioavailability of the API, resulting in efficacy and safety impacts [50,51]. Further studies, such as forced degradation, should be conducted in addition to other spectroscopic techniques (e.g., Fourier-transform infrared spectroscopy, UV-Vis) [52] to better understand the colour differences between the formulations. Another characteristic that can be identified in the optical microscopy images is the greater opacity of the printlet containing 50 wt% PZQ (M 50) compared to the others having only a 35 wt% drug load. When comparing the M 35 Span and M 35 SLS printlets to the respective placebos, the absence of PZQ configures even more transparency. Nonetheless, all printlets presented a good physical appearance, with a smooth surface and shiny finish.
SEM cross-section images of two PZQ printlets (M 35 Span and M 35 SLS) are shown in . They display a dense and homogeneous inner matrix, in which some small holes can be observed. These were most likely formed from air bubbles entrapped during the printing process. The images also provide a clear view of the consistent layers formed by the deposition of material during printing.
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The printlet dimensions and weight are reported in . P 50 and M 50 printlets showed a higher mass variation (0.270 and 0.298 mg, respectively), presumably due to the difference in flow rate (75 and 90%, respectively), as a slower flow rate results in less material deposition. PZQ drug loading was determined only for the M 50 printlets based on the number of units available, and was close to the theoretical load value (48.4%), showing that the dose is approximately 150 mg.
Table 2
Measured Characteristics of PrintletsPrintlet FormulationWeight (g)Diameter (mm)Height (mm)P 50 *0.270 ± 0.029.720 ± 0.223.579 ± 0.05M 50 *0.298 ± 0.019.810 ± 0.163.554 ± 0.14M 35 Span ** 0.297 ± 0.029.982 ± 0.253.507 ± 0.09M 35 SLS **0.290 ± 0.049.841 ± 0.223.591 ± 0.11Open in a separate window
Formulations M 35 with surfactants (Span and SLS) showed a homogeneous flow during the printer feeding process and good uniformity was achieved with regard to physical dimensions ( ). PZQ content values of milled extrudates before printing were 34.84% (M 35 Span) and 33.25% (M 35 SLS). After printing, the results remained similar for both formulations (35.02 and 33.54%, respectively), and with that, the dosages of the printlets were found to be around 100 mg. One of the most discussed applications of 3DP for medicine manufacture is the easy adjustment of dose via the manipulation of the size, structure, or shape of the solid dosage form. The adjustment of the dose by changing the size of 3D printed formulations was already demonstrated in the first clinical study of printlets prepared in a hospital for children [53].
As an initial stage in developing a paediatric pharmaceutical formulation, characteristics such as pharmacokinetics and pharmacodynamics, potential routes of administration, toxicity relationship, and taste preferences should be evaluated [54].
In general, it can be argued that from birth to approximately 16/18 years, individuals are considered paediatric patients [55]. However, when analysing this heterogenous age group, it is easy to see significant differences in the physiological development of the body and the need for personalised medicine development for the different stages of childhood [54]. The 3DP approach can therefore produce different designs, resulting in new dosage forms with specific and unique pharmacokinetic characteristics.
Placebo printlets were also analysed for drug content to check for any possible contamination of printer parts. For all placebo printlets, the presence of PZQ was not identified, thus indicating that cleaning the printer between each batch was effective, with no drug contamination throughout.
3.3. Dissolution Profiles
The dissolution profiles of M 50, M 35 Span, and M 35 SLS printlets show a greater than four-fold increase in drug release after 2 h compared to PZQ alone ( ). It is important to mention that all printlets were printed directly with powdered materials obtained from HME extrudates without the addition of other excipients that could improve properties such as flowability, dissolution, disintegration, and taste masking. This proves that 3DP can be a highly valuable technology for producing personalised pharmaceutical dosage forms to improve physical and sensory properties necessary for a large variety of medicines. The combination of HME and 3DP techniques could be useful to overcome challenges in the formulation development of BCS class II drugs with low solubility, which represent more than 70% of new drug candidates in the pipeline [62].
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It is known from the drug-polymer composition-temperature previously determined by the authors (data not shown) that, at room temperature, 35 wt% PZQ in KOL corresponds to a supersaturated amorphous binary system. Considering that the highest concentration of PZQ (50 wt%) would be sensitive to recrystallisation, in the present study, M 35 Span and M 35 SLS printlets were chosen to be evaluated for taste masking performance using an in vitro biorelevant buccal dissolution method described previously by Keeley et al. [46].
M 35 Span and M 35 SLS milled materials before printing released more than 0.2 mg/mL of PZQ in the artificial saliva in the first minute of the experiment ( a). Münster et al. [63] found that the half maximal inhibitory concentration (IC50) for a PZQ taste response was 0.06 mg/mL when tested with the rat BATA model. The dashed lines indicate the PZQ taste tolerability thresholds they found and are classified as tolerable (0.05 mg/mL) and well tolerable (0.03 mg/mL). Therefore, when ingesting a drug in the particulate form, i.e., a powder formulation for dispersion, the bitter and unpleasant taste of PZQ is likely to be present in the mouth immediately upon administration, at a level triggering aversion. The 3D printed formulations exhibited a significantly lower drug release, even after 600 s, than the M 35 Span and M 35 SLS HME milled extrudates before printing ( a), demonstrating that the 3DP step was key for successful taste masking. As shown in b, both printlets (M 35 Span and M 35 SLS) were below the threshold of good tolerability of the PZQ and even further below the PZQ IC50 (0.06 mg/mL), indicating that the formulations provided efficient taste masking without the use of additional taste masking excipients.
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The bespoke flowthrough oral dissolution apparatus was used in a previous study to evaluate chlorphenamine maleate, a bitter BCS class I drug, incorporated in sugar spheres and coated with different technologies and polymer coatings [46]. In this study, the system could discriminate the taste masking capabilities of the formulations, using taste thresholds generated with the rat BATA model and confirmed with human taste thresholds.
In the case of PZQ, this in vitro taste assessment is a very useful tool to screen formulations and evaluate printlets in early-stage formulation development. The method is simple to execute, relatively inexpensive, and can guide development decisions so that animal experimentation can be reduced as only one taste profiling of the drug is needed. However, although the preliminary results of the printlets are encouraging, there is still the possibility of improving the final formulation with additional excipients to further favour taste masking.
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