The application status of new solid dosage forms for oral administration in children

In recent years, my country has gradually begun to pay attention to the development of children's medicine:

✍In 2011, the "China Children's Development Program (2011-2020) was published;

✍The China National Formulary · Children’s Edition was promulgated in 2013.
In the same year, the “Opinions on Deepening the Reform of Drug Review and Approval and Further Encouraging Innovation” issued by the former State Food and Drug Administration (SFDA) encouraged manufacturers to actively research and develop generic drugs.
Special specifications and dosage forms for children;

✍In 2014, the six ministries and commissions jointly issued the "Several Opinions on Protecting Children's Drug Use", and the SFDA issued the "Technical Guidelines for Pharmacokinetic Research in Pediatric Population" in the same year;

✍In February 2016, the State Food and Drug Administration (CFDA) issued the "Opinions on Resolving the Backlog of Drug Registration Applications for Priority Review and Approval", which stipulates that children's drugs with obvious clinical advantages should be given priority review;

✍In 2018, 22 kinds of medicines for children with urgent clinical needs and definite curative effects were included in the new varieties of the National Essential Medicines List (2018 Edition), which more comprehensively covered the main clinical diseases of children;

✍On June 12, 2020, the Drug Evaluation Center of the National Medical Products Administration of my country issued the "Guiding Principles for the Development of Children’s Drugs (Chemicals) (Draft for Comment)", which filled the gaps in the guidelines for the development of children’s drugs and pharmacy for children The development of drugs provides effective technical support and theoretical guidance;

✍On August 31, 2020, the Center for Drug Evaluation of the National Medical Products Administration will enable the ICH E11 (R1) guidelines to be better implemented in China and help drug developers and clinical researchers to better understand the "Real World Evidence" The “Guiding Principles for Supporting Drug Development and Evaluation (Trial Implementation)” in the application of children’s drug development, released the “Technical Guiding Principles for Supporting Children’s Drug Development and Evaluation (Trial Implementation) by Real-World Research”
.

With the development of the economy and society and the improvement of the quality of life, the development of medicines suitable for children's physiological conditions and convenient for children has attracted more and more attention
.

In order to break through the limitation of the lack of drug dosage forms for children and the bottleneck of current clinical medications, in 2008, the World Health Organization (WHO) proposed at the informal expert meeting on dosage forms for children that micro-solid preparations and disintegrants should be given priority
.

Multiparticulate formulation system

Multiparticulate preparation system refers to a drug delivery system in which multiple discrete pellets with a particle diameter of 0.
05-2 mm are compressed into tablets or wrapped in capsules; for children who cannot swallow capsules, the capsules can be broken apart and sprinkled on apples Take it on the sauce
.

The preparation of new multiparticulate preparations is often used in the development of children's medicines, such as directly dissolving or dispersing the drug in a gelable polymer (such as gelatin) as the core, and semi-permeable, water-insoluble polymer is the drug-containing Coating material for the core
.

Orally Disintegrating Tablets

Orally disintegrating tablet refers to a tablet that can quickly disintegrate under saliva (30s～3 min) after the tablet is placed in the oral cavity, release the drug to form a suspension or solution, and then swallow the tablet
.

The preparation method of orally disintegrating tablets is usually direct compression or freeze drying.
Direct compression is the simplest and most effective method and therefore is the most widely used.
Freeze drying can transform crystalline drugs into amorphous drugs and increase the solubility of the drugs
.

Oral instant film

Oral fast-dissolving films (ODFs) are thin, flexible, and non-breakable polymer films containing one or more active pharmaceutical ingredients (APIs).
When placed on the tongue, they can quickly disintegrate or dissolve in saliva.
, And then swallow into the gastrointestinal tract
.

The most commonly used preparation method of ODFs is solvent casting method, which has the characteristics of simple operation and low cost.
In addition, ODFs can be prepared by electrospinning technology.
The drug is mixed with polymer solution, and under the action of strong electric field force, it overcomes the problem of polymer Surface tension, the formation of sub-micron polymer fibers, and the high surface area/volume ratio of nanofibers can improve the defect of low drug loading of the instant membrane agent
.

Microchip

Microtablets with a diameter of no more than 3 mm are microtablets, which can be used in combination with other dosage forms, such as orally disintegrating microtablets (ODMTs)
.

Chewable tablets

Chewable tablets need to be chewed in the mouth first to produce a pleasant taste and then swallowed instead of swallowing the whole tablet, which improves the absorption of the drug and the compliance of children's medication
.
In order to reduce the bitter taste of the drug in the mouth, sweeteners such as maltose and sucralose can be added to mask the taste
.
Chewable tablets are usually prepared by wet granulation.
The drug can be mixed with a polymer with good flexibility and ductility and then granulated, then mixed with fillers, flavoring agents and other auxiliary materials to granulate, and finally compressed into a slow controlled tablet.
Release chewable tablets
.

Medicinal chewing gums (MCGs)

MCGs refer to solid single-dose preparations with chewing gum as the main substance, which slowly and stably release the drug through chewing, which can be used to treat oral diseases or exert systemic effects through the oral mucosa
.
It consists of two phases, namely, a water-soluble continuous phase containing non-chewable ingredients and a water-insoluble discontinuous phase dominated by chewable ingredients.
Its specific components include water-insoluble discontinuous phase elastomers, anti-sticking agents, and elastic Body solvents, emulsifiers, waxes, plasticizers and fillers, as well as water-soluble continuous phase sweeteners and flavors
.
Studies have found that the drug-containing particles after alginic acid-starch microencapsulation and then coated with chitosan can realize the gradual release of the drug from the MCGs, which can avoid the sudden release of the drug in the early stage of chewing, and make the patient more receptive to the drug.
It has a bitter taste and does not cause gastrointestinal discomfort
.

Dispersible tablets

Dispersible tablets refer to tablets that are taken after being dispersed in a small amount of water or milk
.
For children under 5 years of age, the liquid should not exceed 5 mL; for children over 5 years of age, the liquid should not exceed 10 mL
.
Adding a small amount of thickener to the dispersible tablet can not only prevent the excipients and drug particles in the dispersible tablet from rapidly settling after disintegration, but also can mask the graininess and give it a good mouthfeel
.
For poorly soluble drugs, a small amount of skimmed milk powder and surfactant Tween 20 can be added to the excipients, and freeze-dried to make dispersible tablets, because the casein in the milk powder can form micelles with the assistance of Tween 20 to increase the solubility of the drug.
And the surfactant itself can also improve the solubility
.
Dispersible tablets can also be prepared by layer-by-layer 3D printing technology (a layer of medicated powder, a layer of wetting agent).
This preparation method does not require compression to prepare loose and porous dispersible tablets.
The tablets are quickly dispersed in the mouth and swallowed.
The dosage is accurate
.

In recent years, oral solid preparations for children have gradually diversified, and more solid preparations suitable for different ages have appeared
.
Among them, multiparticulate preparations and dispersible tablets can be used for newborns.
Oral quick-dissolving films are more suitable for younger children than orally disintegrating tablets.
Children over 2 years old can use chewable tablets, microtablets and orally disintegrating tablets, while 6 years old and above can use chewable tablets, microtablets and orally disintegrating tablets.
Only children who are younger can take capsules and medicinal chewing gum
.
In addition, in addition to the diversification of dosage forms, the compliance of children's medications and the accuracy of dosages have also been improved
.

Reference materials:

[1]Sun Jundi, He Shuwang, Yao Jing.
Research progress on new solid dosage forms for oral administration in children[J].
Journal of China Pharmaceutical University, 2019, Volume 50, Issue 6, Pages 631-640, ISTIC PKU CSCD, 2019.

[2]Xu Jiangkang, Hu Xuefang, He Shuwang, et al.
Research progress of drug formulations for children[J].
Chinese Journal of New Drugs and Clinical Remedies, 2016(12):841-846, 6 pages.