Mini Tablets: Pediatric Drug Delivery System

 

Bhuvaneshwari S, Umashankar M S*, Damodharan N

Department of Pharmaceutics, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur-603203.

 

ABSTRACT:

 

 

INTRODUCTION:

Pediatric require various oral drug delivery than different subsets of the population because of their persevering with development consequently dosing and administration requirements. General formulations are not intended for pediatrics, as a consequence, manipulation and compounding has end up traditional approach. Age-appropriate oral drug delivery systems mainly advanced to fulfill the requirements of the pediatric population are therefore preferred. The pharmacokinetic and pharmacodynamic profile of a drug varies extensively depend on the developmental period of a infant, considerate dose flexibility to healthful dosing requirements throughout in all ages [7,8].

 

The sapidity of pediatric drug treatments is the maximum crucial formulation factors in the acceptation of liquid formulations with capacity to impact adherence to healing regimens and consequences. Palatability is defined as, ‘the general appreciation of a (frequently oral) medicinal over lusciousness properties such as vision (appearance), scent, mouth feel, taste and aftertaste. [9,10] taking into consideration that delivery of drug in children can be hard for caretakers and mostly meals is used to help out the method, it's far worthwhile to investigate specific dosing eventualities, as well as suitable gastrointestinal digestion models. Blending tablets into nutrients is one method to moreover mask the taste of drugs and make it easier the swallowing system. Anyway, a numerous aspect along with the viscosity and pH range as well as fats and sugar contents have to be considered and evaluated. [11,12]

 

Mini tablets:

Mini tablets are smaller doses with a radius commonly measures 3mm or less than 3 mm which are capable of filling into capsule, or rarely, may be compressed into large tablets. These mixtures may consist of immediate delivery, sustain release, and/or control delivery system there is also the possibility to embody mini tablets of various drugs to heal synchronous diseases or combinations of drugs to enhance average therapeutic effect. [13,14]. The widely used preparations for pediatrics are liquid dosage forms, which is secure and without difficulty given to pediatrics, but masking the bitter taste and bulkiness in formulation is the important challenging. Mini tablets prove to be a unique method of pediatric oral drug delivery system. [15,16]

 

Figure1: Minitablets

 

Table 1 : Pediatric diseases

Disease	Disease condition	Caused by	Treatment
Tetanus	Neurological disorder with autonomic disturbances, muscle spasms and spasticity	Clostridium tetani  Which produces ‘tetano-spasmin’ (neurotoxin)	Penicillin, Metronidazole, Vaccine-c.tetani [17,18]
Rhinovirus	Viral respiratory tract infection along with the coin infection	Rhinovirus (causative agent) belongs to family icornaviridae	Pseudoephedrine, oxymetazoline, anti-histamines, NSAIDS [19, 20]
Acute respiratory distress syndrome	Respiratory failure,	Severe inflammation of the lung paren­chyma, Hypoxemia	Mechanical ventilation (mev), tracheal intubation [21, 22]
Poliomyelitis	Aseptic meningitis, Nonspecific febrile illness, paralytic disease.	Virus picornaviridae	Tracheostomy, mechanical ventilation (mev) [23,24]
Pertussis	Paroxysmal cough, inspiratory whoop, and post-tussive vomiting	Gram-negative Coccobacillus- bordetella pertussis	Erythromycin estolate, Macrolides antibiotics, trimethoprim-sulfamethoxazole [25, 26]
Parainfluenza	Bronchitis, pneumonia	Negative‑sense RNA viruses belong to family Paramyxoviridae	Budesonide, ribavirin [27, 28]
Necrotizing enterocolitis	Wheezing, bronchiolitis pneumonia,	Enveloped, non-segmented, negative-sense, single-stranded RNA viruses	Ribavirin, immunoglobulin. [29, 30]
Measles	Otitis media, pneumonia, Encephalitis, conjunctivitis	Genus morbillivirus in the paramyxoviridae Family	Vitamin a, antipyretic agents [31]
Diphtheria	Myocarditis, poly neuropathy	Toxigenic corynebacteria diphtheriae	Antitoxin, a horse antiserum, penicillin [32]
Cytomegalovirus infection	Nonhereditary sensorineural hearing loss, chorioretinitis, pneumonia, colitis, and neuropathy.	Large, linear, double-stranded DNA human herpes virus family	Ganciclovir triphosphate, valganciclovir [33]
Candidiasis	Non-life threatening Mucocutaneous disorders, bloodstream infection	Yeast from the genus candida albicans	Amphotericin b deoxycholate, lipid complex amphotericin, Fluconazole [34]

 

Advantages of mini tablets:

·       Reduced dose dumping.

·       They offer excessive drug loading.

·       They can be prepared reproducibly.

·       It possesses intra and inter-subject variability.

·       Manufacturing of mini tablets are comparatively easy.

·       They have smooth surface, size uniformity and regular shape.

·       In modified release the substrate produced by mini tablets flexible to coat with polymeric membranes. [35]

 

Types of mini tablets:

Mini tablets are categorized in accordance with target site,technique of producing and patient requirements

 

Figure 2: Types of mini tablets

Pediatric mini tablets:

Other than tablets, syrup and capsules, mini tablets are easily accepted by children. Mini tablets provide good patient acceptance with overcoming above difficulties

·       Syrups-it can be altered according to patients need, the major disadvantages are physical, chemical, microbial fluctuations, taste related issues, and insufficient controlled release and formulation problems.

·       Tablets-swallowing may be difficult, breaking of tablet may lead to loss of activity

 

pH responsive mini tablets:

There are different pH value for gastro-intestinal tract stomach pH 1.5-3.0, Duodenum pH 4.0-5.0, Small intestine jejunum and ileum pH 6.5-7.5, and colon pH 5.6-6.9. pH responsive drugs are needed when absorption take place at specific site. Coating the tablet with pH responsive release polymer provides activity. Examples of pH responsive polymer are Eudragit L100 and Eudragit S100

 

Oral disintegrating mini tablets:

An oral dispersible tablet (ODTs) does not require water to disintegrate or need to be chewing during intake. Rather rapidly disintegrates in mouth within 1-3 minutes. The disintegrated tablet should provide smooth swallowing and good mouth feel, after administration it should be liquid suspension or soft paste. Taste masking technique is used if the drug has undesired taste or tasteless

 

Gastro retentive or floating mini tablets:

Gastro retentive mini tablets are the formulations which deliver the drug to stomach to provide prolong duration. When tablets react with food, carbon dioxide is formed and the tablet floats in gastro intestinal fluid at stomach where the gas is trapped in swellable hydrocolloid due to the presence of gas generating agent in the formulation.[45]

 

Bio-adhesive mini tablets:

Bio-adhesive mini tablets are widely utilized for vaginal drug delivery system to provide long period of time and drug accuracy. The multi doses are evenly spreads over vaginal cavity along with enhanced covering of vaginal epithelium. Maximum bioavailability is achieved by drug released in a controlled release system. Bio-adhesive mini tablets possess activity by enlargement and the formation of micro gels.

 

Bi phasic mini tablets:

Bi phasic mini tablets constitute two portions,

·       Bust releasing-immediate release of drug after administration,

·       Slow releasing-release of drug in controlled manner.

It is useful in treating hypertension due to reduced repeated dosing. Treatment of different disease can be carried out by compressing different drug of mini tablets and filled into the capsules.

 

Colon targeted mini tablets:

Chron’s disease, irritable bowel syndrome, and ulcerative colitis are the local bowel diseases that can be treated by targeting the drugs into the colon. The specific impact of drugs on a particular region decreases the side effects and moderate enzyme action in the end. The aforementioned admits protein and peptide structured drugs to be fortunately employed with colon targeted methods. The difficulties like sudden disintegration and drug loss in the GI tract occur if single unit drug delivery systems are targeted to the colon.

 

Pulsatile and Bimodal Release:

Pulsatile drug delivery system comes under the category of a prolonged-release which is a time-dependent and site-specific system to reach the chronotherapy requirement. The polymer with the controlled release is useful for coating the tablet to achieve the pulsatile release. The coating serves as a protective film during the comparison of a drug with the aqueous medium. This coating produces a fragile, erodible, penetrable, and semipermeable layer coating. This system has a huge metabolization on the first-pass impact and hinders the synergy of drugs within the GI tract. Pulsatile drug release is useful for treating diseases like bronchial asthma, angina pectoris, and sleep disorders. The bimodal release system gave single-unit methods like layered tablets and multi-unit methods like pellets and mini tablets also produces a volatile release. It comprises the first fast discharge and a steady slow discharge time accompanied by a next active release stage beside a sigmoidal release form. The rapid absorption of drugs occurs and uniform release in the entire GI tract. Though, partially slow absorption in the stomach, fast in the proximal part of the gut, and further slow in the distal part of the gut. Because of the above understanding, the release rate of a drug may either increase or decrease in specific areas to attain a uniform drug blood concentration.[3]

 

Manufacturing of mini tablets:

 

Figure 3: Different methods to manufacture mini tablets

 

 

Table 2: Various dosage forms

	Liquid dosage form	Solid dosage form
Concept	Liquid dosage form contains one or more soluble chemical substances dissolved in specified solvent	Solid dosage form containing medicaments with or without the excipients
Dose flexibility	Can be easily swallowing due to the enhanced dose flexibility. Multiple doses required to be administered throughout the day	provides long term stability but swallowing may be difficult in case of pediatric patient
Administrative devices	Baby bottle coupled to a syringe, dose sipping syringe	Pill swallowing cups
Formulations	Solutions, suspension, emulsion	Powders, granules, sprinkles [36,37]

 

Direct compression method:

In direct compression method the drugs with powder are blended, which contains excipients and API that are compressed directly into bi-convex mini tablets. Good quality excipients are used to get the desirable hardness. Direct compression provides more stability than the tablets formulated by wet granulation.[44]

 

Wet granulation method:

In wet granulation method, granules are formed by the use of binder solution and compressed to get mini tablets. Binding agents with different grades are utilized. Mostly polyvinyl pyrrolidone is used as binding agent.

 

Dry granulation method:

Dry granulation method is used for thermo-labile and moisture-sensitive drugs. Roller compactor or chilsonator is equipment used in the compression process. The compression of premixed powders carried out in the form of ribbon or sheet according to the roller structure. The granules are mixed with in-active excipients and then compressed in rotary compression machine.

 

Melt extrusion method:

In melt extrusion method, the premixed powder which contains excipients and API is transferred to melt-extruder. The extrudates are milled and sieved according to the parameters like feed rate, screw speed and temperature. The granules are then compressed using compression machine. [1]

 

Preformulation studies:

This study carries analytical and pharmaceutical review along with propping the formulation improvement response of dosage forms of the drug substance. Knowledge about the constitution of substance and drug with excipients combination are acquired.

 

Figure 4 : Various Preformulation studies of mini tablets

 

Angle of repose:

It is determined using funnel and the cone technique. where the funnel is fixed at given height(h) and positioned on flat surface measuring 2cm over the graph paper.

 

Bulk density and tapped bulk density:

2grams of the granules examined earlier for agglomerate and then brought into a 10ml measuring cylinder. Initial volume is noted and tapped at several intervals until and then volume remains unchanged. The LBD and TBD can be calculated by

 

(LBD-Loose Bulk Density, TBD-Tapped Bulk Density)

 

LBD = Weight of the powder/volume of packing

 

TBD = Weight of the powder/Tapped volume of the packing.

 

Compressibility index:

Carr’s index is determined by compressibility index of granules

 

Carr’s index (%) = [(TBD-LBD) * 100] / TBD

 

Hausner’s ratio:

Hausner’s ratio states the flow properties of the powder and can be determined by Hausner’s ratio = TBD / LBD [38]

 

Evaluation of mini tablets:

Weight Variation Test:

Selecting and randomly weighing 20 mini tablets from the batch and note down the individual weight of all tablets. Then, calculate the average weight plus compare the individual weights over the average. As per the USP, tablets average weight should range from 90% to 110%. 10% is an allowable specification regarding weight variation.

 

Hardness:

Pfizer hardness tester is useful for determining the hardness of the mini tablets. The unit of hardness is kg/cm2. Randomly pick the six mini tablets to test the hardness. Calculate the mean and standard deviation values of all formulation.

 

Thickness:

The digital caliper (Mitutoyo digimatic caliper) plus screw gauge is useful for measuring the thickness of the mini tablets and expressing the unit in terms of a millimeter. Select 10 tablets from each batch and record the individual thickness of the tablets in mm. From the recorded value, one can calculate the mean and standard deviation values.

 

Friability:

Roche/veego friabilator is suitable for conducting the friability test. From each batch, randomly select 20 mini tablets and note down the initial weight then transfer it into a friabilator. Rotate the drum at 25rpm for about 4 mins later remove those tablets. The soft brushes are useful for removing the loose dust, and again reweigh the mini tablets.

 

Drug content uniformity:

5 mini tablets are weighed and crushed in a mortar. The crushed powder is weighed equivalent to the 10mg of drug and transferred to the 100ml of dissolution medium to produce 100μg/ml concentrations. From this solution, 15ml is dilute to 100ml to provide a 15μg/ml concentration and the absorbance is measured using of UV-visible spectrophotometer with desired wavelength.

 

In-vitro disintegration:

According to the Indian pharmacopeia specifications, the disintegration test apparatus was useful to determine the in-vitro disintegration of the mini tablets. In each tube, tablet and the disc are added and immersed in 900ml of dissolution medium at 370 ͦC. Time noted to determine the complete disintegration of the tablet and the absorbance is measured using UV- visible spectrometer.

 

In-vitro drug release:

The drug release is studied by utilizing USP dissolution test apparatus I at 100rpm and pH of about 1.2 buffers in 900ml of 0.1 N hydrochloric acid for 2 hours. The replacement of the dissolution medium pH 6.8 phosphate buffer and then continuing for 10 hours. About 5ml of samples are withdrawn from the dissolution medium and replacing with another 5ml of fresh medium at different time intervals. The samples is analysed in a UV spectrophotometer with the desired wavelength. [39]

 

Tooling:

When it comes to tablet compression, single tip tooling is widely used for conventional tablet. But, for multi-unit dosage multi tip tooling is employed. Numerous tablets are produced at times due to several tips in same punch.

 

Benefits of multi tip tooling:

·       Productivity is increased,

·       Only mold cost other than that no other production equipment’s required,

·       By using the multi tip punches working time are reduced,

·       Products are collected which does not requires any separate equipment’s.

·       The expense of the process is low when done with the above features.

 

There are two varieties of fixing internal cap fixing and external cap fixing. Multiple punches are utilized as multi piece assemblies or as monoblocks. The internal fixing pins are immobilized into the punch body. Mounting and disassembly of them are easy and they have fewer pins compared to external cap fixing.

 

Table 3 : Difference between multi piece assembly and monoblock

MULTI PIECE ASSMEBLY	MONOBLOCK
The risk of contamination of the product is less	This require less installation time
Before cleaning, parts should be separated.	Easier to clean.
These are resistant to breakage and abrasion,	Monoblocks are more resistant.

(The length / diameter ratios and the speed of the device have to be adjusted well)

 

Figure 5: Different Multi Tip Punches to Compress Mini Tablets

 

Table 4: Marketed mini tablets/encapsulated mini tablets

Generic name	Brand Name	Formulation
Donepezil Hydrochloride	Aricept	Mini tablets
Levonorgestrel and Ethinyl Estradiol	Alesse	Mini tablets
Sumatriptan and Naproxen Sodium Tablets	Treximet	Mini tablets
Pancrelipase	Ultresa	Mini tablets/encapsulated mini tablets
Zafirlukast	Accolate	Mini tablets
Galantamine Hbr Er	Razadyne ER	Mini tablets/encapsulated mini tablets
Hydromorphone Hydrochloride Extended Release Tablets	Exalgo	Mini tablets
Warfarin Sodium	Coumadin	Mini tablets
Fenofibric Acid Capsules	Trilipix	Mini tablets/encapsulated mini tablets
Vorapaxar Tablets	Zontivity	Mini tablets
Prasugrel Tablets	Effient	Mini tablets
Olanzapine	Zyprexa, Zyprexa Zydis	Mini tablets

Packaging:

The packaging pattern of mini tablets is specifically determined by the product design requirements or target product profile. The preference of accurate packaging form additionally relies upon on drugs product overall performance in a selected packaging configuration at some stage in long time storing. There are various methods to deliver mini tablets to the patients, thou consist of encapsulation in capsule shells, stick-packs or sachets are used to pack along with the unit dose packaging, or prefilling a container for disintegration. [40]

 

Limitation:

There’s a predicament on drug load in mini tablets and oral films; with respect to pediatrics, although, lower, and greater critical flexible doses are required in maximum cases, specifically for neonates. Based on the mini tablets size, it may weigh only 6 mg, which restricts the drug load capacity for each tablet. In case of large amount drug load in films may lead to slower disintegration and increased thickness and require individual characterization with respect to their suitability attentive assessment is required in terms of sustained release formulations. Coatings of drug-loaded granules might also rupture at some stage in processing or chewing, which may additionally have an impact on the release profile and the taste-covering outcome. [41]

 

Idea of administering mini tablets:

Administering tablets to the pediatric patients is still a challenging but mini tablet have proven to overcome all those difficulties. Regularly children need vitamins, proteins and nutrients hence these all can be formulated as mini tablets which can be mixed along with food, milk etc. Other than that formulation of medicines as mini tablets in pediatric healthcare products like cerelac, drink mix, Kellogg’s will be useful for the pediatric oncological patients. Idea of formulation

·       Gummy bears- flavored gummy candy

·       Lollipop- lozenges on stick [42]

·       Gems – medicine on inner stuff[43]

 

CONCLUSION:

The conclusion of this review clearly shows the advancements in mini tablets for the pediatric patients. Accurate dosage of medicines is delivered to the pediatric patients. Mini tablets are multi-unit dosage forms which are better than the single unit dosage form and also great alternative of granules and pellets. Defined shape, size, surface, low degree of porosity and high mechanical strength are possessed by the mini tablets. Concurrent disease can treat by combining various mini tablets hence incompatible drugs can be administered.

 

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Accepted on 29.02.2020           © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(6): 2985-2991.