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Tablets & Capsules SDD
 
More Questions and Answers
 
Mini-tablets
 
Q: What are the advantages of mini-tablets for pediatric and geriatric patients?
 
 
imageDeveloping a drug product for pediatric or geriatric patients is often challenging because a single product may not be viable for all patients within each group. In both groups, swallowing abilities and taste preferences make choosing dosing regimens for traditional solid dosage forms more challenging.
 
Challenges of large pills
In the case of antiretroviral therapy (ART), patients may have to take three or more solid doses or a combination of solid and liquid doses every day, twice a day. Many studies have found swallowing tablets or capsules to be a barrier to adherence for children and elderly patients [1-3]. Studies have demonstrated how caregivers take measures into their own hands to overcome these challenges, documenting that they open capsules and crush tablets and sprinkle the contents into food [4, 5]. Crushing tablets or opening capsules can reduce the bioavailability of ART because the patient may not receive the entire contents, significantly reducing the targeted therapeutic exposure. This can reduce viral suppression and promote viral resistance and ultimately lead to a failed treatment regimen [6].
 
Many studies have looked for solutions to the issues related to swallowability, such as alerting patients and caregivers about the problems that opening capsules and combining medications with food can cause, identifying which products are dispersible in water, and offering swallowing training for patients. Gastrostomical tube insertion for medication delivery is a more drastic and invasive solution to administering solid dosage forms to patients who are unable to swallow solid or liquid medications [7].
 
These challenges support the need for easy-to-swallow medications, such as sprinkles or more palatable, flavored liquids for young children or elderly patients. In addition, regulatory agencies across the world are insistent about the need for research into the design of novel, age-appropriate dosage forms. By keeping these difficulties in mind, often pharmaceutical companies can develop acceptable dosage forms, typically formulated as powders for suspension, oral granules, oral solutions, or most recently, mini-tablets.
 
Advantages of mini-tablets
Dosages. Due to the ease of administration, liquid formulations are most commonly prescribed to patients with swallowing difficulties. To eliminate problems related to liquid dosage forms—such as chemical and microbial instabilities and lack of accuracy in dosing—and with the aim of improving drug delivery for pediatric and geriatric populations, pharmaceutical companies have developed mini-tablets as a patient-friendly dosage form.
 
In the absence of strict regulatory guidelines, pharmaceutical companies consider mini-tablets to be tablets that are smaller than regularly sized tablets but that have typical diameters from 1 to 5 millimeters. Companies sometimes use the terms micro-tablets, oral granules, or sprinkles interchangeably with the term mini-tablet due to the similarities in their sizes. Coated or uncoated mini-tablets are more appropriate than traditional tablets or capsules for pediatric and geriatric patients because they offer improved swallowing and flexible dosing, combining various release kinetics, doses, and active compounds in a single dosage form.
 
Customized delivery. Mini-tablets allow customized delivery in terms of a combination of release rates and mechanisms as well as targeted release to different segments of the GI tract. One dosage form can incorporate a number of mini-tablets, each one formulated individually and programmed to release a drug at a different site in the GI tract.
 
These combinations can include immediate release (IR), delayed release, and/or extended release (ER) mini-tablets [8, 9]. For instance, in one study, Butler et al. filled a final capsule product with nine mini-tablets combining three intermediate components: IR mini-tablets, ER mini-tablets targeted to release a drug in the upper small intestine, and ER mini-tablets targeted to release a drug in the lower small intestine.
 
Combination therapy. Mini-tablets also provide the opportunity to create a multi-particulate dosage form that can include more than one API and be used as a combination therapy. To create this form, formulators can incorporate each API into its own minitablet and then place all mini-tablets in one capsule, sachet, or stick-pack dosage form.
 
Disintegration times. Additionally, the small size of mini-tablets enables rapid disintegration times. This permits their use as an orally disintegrating dosage form when properly formulated and allows their dispersion in a liquid prior to administration, which is appropriate for young children or infants who can swallow only disintegrated particulates [10].
 
Product design. From a product-design perspective, mini-tablets offer potential advantages. For instance, Guggi et al. prepared mucoadhesive mini-tablets containing a peptide-structured calcitonin compound, targeted to the stomach. This formulation used thiolated chitosan as a mucoadhesive polymer, glutathione as a penetration enhancer, and chitosan-pepstatin conjugate as a peptide-protecting agent. The researchers administered the peptides orally to determine the pharmacological effects [11].
 
In another study, Goole et al. developed floating mini-tablets using high-viscosity hydroxypropyl methylcellulose (HPMC) as a swellable hydrocolloid to trap the carbon dioxide that the gas-generating agents created and to extend the release of the drug. These mini-tablets remained buoyant until their complete erosion, which ensured their floating capabilities, until the end of drug release [12].
 
Similarly, Iannuccelli et al. designed multi-unit floating systems with air compartments, separated by a calcium-alginate core and a membrane of calcium alginate or calcium alginate/polyvinyl alcohol (PVA). These systems showed improved in vitro and in vivo performance compared to a single-unit system [13, 14].
 
Additionally, researchers have used mini-tablets as controlled-release ophthalmic inserts containing timolol maleate, where the researchers applied a thin, rate-controlling membrane over the devices by spraying aqueous dispersions of acrylic copolymers (Eudragit RS; Eudragit RL) [15].
 
Excipients. In another instance, Stoltenberg and Breitkreutz studied orally disintegrating mini-tablets (ODMTs) as a suitable dosage form for pediatric patients. In their study, the researchers examined the suitability of five commercially available, ready-to-use, co-processed tableting excipients based on mannitol—Ludiflash, Parteck ODT, Pearlitol Flash, Pharmaburst 500, and Prosolv ODT—that they directly compressed into 2-millimeter mini-tablets. They investigated drug-free ODMTs and ODMTs with a child-appropriate dose and found that they could produce ODMTs with all investigated excipients. These promising results indicated that ODMTs may serve as a novel platform technology for pediatrics in the future [9]. Table 1 presents some examples of commercially available mini-tablets.
 
Table 1. Examples of commercially available mini-tablets
 
Brand Name Drug Name Indication Manufacturer Dosage Form
Rythmol SR Propafenone HCl Antiarrhythmic GlaxoSmithKline Capsule
Enzym-Lefax Pancreatin Indigestion Bayer Capsule
Lamisil Oral Granules Terbinafine HCl Antifungal Novartis Sachet
Orfiril long Sodium Valproate Epilepsy Desitin Capsule, Sachet
Pankreatan Pancreatin Pancreatic insufficiency Novartis Capsule
Trilipix Fenofibric acid Cholesterol Abbott Capsule
Kalydeco Ivacaftor Cystic fibrosis Vertex Stick pack
 
Manufacturing processes. Depending on the nature of the API, the most common manufacturing processes for mini-tablets include blending and granulating, compression of the final blend into mini-tablets, and coating of core mini-tablets.
 
Packaging. The target product profile or the required product-design criteria determine the packaging configuration of mini-tablets. The selection of the correct packaging configuration also depends on the drug product's performance in a particular packaging configuration upon long-term storage. The delivery of core or coated mini-tablets to patients can include encapsulation or unit-dose packaging, such as stick-packs or sachets.
 
Since most mini-tablets will be oral medications within pediatrics and geriatrics, the Stevanato Group, previously the Balda Group, has developed solid dispensing systems that make it possible for patients to take their medication accurately, safely, and conveniently. The smart mini-tablet dispenser (sMTS) is a re-usable dispenser with a flexible and open design, which allows modification according to a tablet's characteristics and other requirements. The patient, caretaker, or nurse can easily adjust the number of mini-tablets per dosage at home based on the dose required or a pharmacy can pre-fix them, with space for up to 20 units. This device supports the acceptance of mini-tablets at home, by patients and caregivers.
 
Caregivers. In addition to better adherence, mini-tablets as a dosage form can reduce the time and energy required of caregivers to administer medication. As discussed previously, caregivers can easily spill liquid medications, and it is time-consuming for them to measure an accurate dose. Innovations such as sprinkles, dissolvable mini-tablets, mini-tablet dispensers, and sachets of mini-tablets can decrease the mess and reduce the time it takes to prepare medications by allowing caregivers simply to mix the drug product with soft foods like puree or yogurt.
 
Challenges of mini-tablets
Caregivers. Small tablets might not be appropriate for patients with motor impairment, unless administered in clinical settings or with the help of a caregiver or a dosing device. Due to their small size, patients and caregivers can more easily drop or lose mini-tablets compared to traditionally sized tablets, which may lead to an accidental loss of dose.
 
Manufacturing. A few potential challenges exist in working with mini-tablets as an age-appropriate dosage form. The most notable issue with mini-tablets is their small size, which makes them difficult to handle individually during a manufacturing operation or during analytical testing in the lab. The large number of units per batch and the number of units required for testing are significantly higher compared to those of traditional tablet development.
 
From a manufacturing perspective, pharmaceutical companies must package multiple mini-tablets together to provide a single dose, which lowers the dose-based production rate. As such, minitablets seem best implemented for small-volume, high-value products, especially for specific patient populations that can benefit from their distinguishing features [16].
 
Summary
Mini-tablets used as single- or multiple-unit oral dosage forms have enormous potential as a patient-friendly drug delivery system for targeted populations, providing improved swallowing, flexible dosing, and a combination of different release patterns and/or different active compounds. As an age-appropriate dosage form, mini-tablets provide satisfactory characteristics regarding safety and acceptance, and convenient administration, which children, especially infants, and elderly patients need.
 
Despite the mini-tablet's benefits as a dosage form, their popularity is limited due to a lack of formulation and processing knowledge about them. The type of dosage form required, the material properties of APIs and excipients, and the factors related to the manufacturing process mainly dictate the development of mini-tablets as drug products.
 
Further investigation of formulation possibilities and development of suitable dosing devices is of essential importance.
 
References
  1. Shingadia D, Viani RM, Yogev R, et al. Gastrostomy tube insertion for improvement of adherence to highly active antiretroviral therapy in pediatric patients with human immunodeficiency virus. Pediatrics. 2000; 105(6), article E80.
  2. Buchanan AL, Montepiedra G, Sirois PA, et al. Barriers to medication adherence in HIV-infected children and youth based on self- and caregiver report. Pediatrics. 2012; 129(5):e1244-e1251.
  3. Pontali E, Feasi M, Toscanini F, et al. Adherence to combination antiretroviral treatment in children. HIV Clinical Trials. 2001; 2(6):466-473.
  4. Best BM, Capparelli EV, Diep H, et al. Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children. Journal of Acquired Immune Deficiency Syndromes. 2011; 58(4):385-391.
  5. Bunupuradah T, Wannachai S, Chuamchaitrakool A, et al. Use of taste-masking product, FLAVORx, to assist Thai children to ingest generic antiretrovirals. AIDS Research and Therapy. 2006; 3(1), article 30.
  6. Manjari L, Manshun L, Marcus E, Changcheng Z. Developing a flexible pediatric dosage form for antiretroviral therapy: A fast-dissolving tablet. J. Pharm. Sci. August 2017; 106(8):2173-2177.
  7. Li Y-h and Zhu J-b. Modulation of combined-release behaviors from a novel tablets-in-capsule system. J Control Rel. 2004; 95:381-389.
  8. Ishida M. Abe K, Hashizume M, Kawamura M. A novel approach to sustained pseudoephedrine release: Differentially coated mini-tablets in HPMC capsules. Int J Pharm. 2008; 359(1-2):46-52.
  9. Stoltenberg I and Breitkreutz J. Orally disintegrating mini-tablets (ODMTs) - A novel solid oral dosage form for pediatric use. Eur J Pharm Biopharm. 2011; 78(3):462-469.
  10. Butler J, Cumming I, Brown J, Wilding I, Devane JG. A novel multiunit controlled-release system. Pharm Tech. March 1998;122-138.
  11. Guggi D, Krauland AH, Bernkop-Schnürch A. Systemic peptide delivery via the stomach: In vivo evaluation of an oral dosage form for salmon calcitonin. Journal of Controlled Release. 2003; 92:125-35.
  12. Goole J, Hamdani J, Vanderbist F, Amighi K. In vitro and in vivo evaluation in healthy volunteers of a new sustained-release floating dosage form. 2006a; Fifth World Meeting on Pharmaceutics, Biopharmaceutics, and Pharmaceutical Technology, Geneva, Switzerland.
  13. Iannucelli V, Coppi G, Sansone R, Ferolla G. Air compartment multiple-unit system for prolonged gastric residence. Part II. In vivo evaluation. International Journal of Bioapharmaceutis. 1998; 174: 55-62.
  14. Iannuccelli V, Coppi G, Bernabei MT, Cameroni R. Air compartment multiple-unit system for prolonged gastric residence. Part I. Formulation study. International Journal of Biopharmaceutics. 1998; 174:47-54.
  15. Satteone MF, Chetoni P, Mariotti Bianchi L, Giannaccini B, Conte U, Sangalli ME. Controlled release of timolol maleate from coated ophthalmic mini-tablets prepared by compression. Int J Pharm. 1995; 126:79-82.
  16. Alfred C. F. R, David H, Francis F, Varsha B, Mary AJ, Dina Z, Sanjaykumar P. Minitablets: Manufacturing, characterization methods, and future opportunities. American Pharmaceutical Review. July 30, 2016.

Anthony Qu is vice president of scientific affairs at Halo Pharmaceuticals.
 
May 21, 2018
 
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