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Innovative drug development ideas for topical skin preparations

2022-09-13
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Traditional plasters such as black ointment, which have been widely used in China throughout history, belong to the category of transdermal drug delivery. However, they are mainly proprietary Chinese medicines with low drug loading capacity, unknown pharmacology, and high side effects. In the 1970s, modern transdermal drug delivery formulations emerged in the United States and Japan. Transdermal drug delivery is a prospective drug delivery strategy that can compensate for the limitations of traditional drug delivery systems.

Medicilon can undertake the development process of various topical skin preparations, including ointments, creams, gels and other semi-solid preparations, as well as lotions, liniments and other solutions. Equipped with corresponding transdermal and testing instruments (Such as LC-MS/MS), medicilon can provide professional and efficient services in projects involving in vitro evaluation such as compound screening, new drug submission, pharmacological changes of marketed chemical drugs, consistency evaluation, and generic drug submission.

Learn more about "Medicilon Skin Topical Preparation R&D Platforms"

Transdermal drug delivery principle

Transdermal drug delivery system (TDDS) or transdermal absorption formulation, refers to the administration of drugs on the skin surface, where the drug enters the circulatory system at a constant rate (or near continuous rate) through the skin surface, and the transdermal absorption formulation can play both local and systemic therapeutic roles. Transdermal drug delivery systems include patches, ointments, hard creams, coatings, and aerosols.

The skin is mainly composed of the stratum corneum, the growing epidermis, the dermis, and the subcutaneous tissue (the stratum corneum and the ever-increasing epidermis are called the epidermis). It also includes accessory organs such as hair follicles, sebaceous glands, and sweat glands. The epidermis can be divided from the inside out into stratum corneum, stratum hyaline, stratum granulosum, stratum spinosum, and stratum basale. Among them, the stratum corneum comprises dead keratinized cells and fibrinogen proteins, the main barrier affecting drug absorption. The percutaneous absorption of drugs is mainly driven by passive diffusion through the difference between the drug concentration on the skin surface and the drug concentration in the deeper layers of the skin.

1 Schematic diagram of human skin.webp

Schematic diagram of human skin [1]

The process of transdermal drug absorption is as follows:

(1) Drug diffusion to the stratum corneum;

(2) Drug diffusion in the stratum corneum;

(3) Drug diffusion in the epidermis and dermis;

(4) Drug absorption by capillaries in the dermis;

(5) Drug enters the body's circulation with blood.

Transdermal drug delivery development

First generation: diffusion-based transdermal drug delivery

Since the FDA approved the transdermal patch of scopolamine (Transderm scop) in 1979, several drug transdermal formulations have been marketed. However, due to the physiological barrier of the epidermis, the number of drugs suitable for patch formulation is severely limited. Most first-generation transdermal drugs are highly lipophilic, with partition coefficients more significant than 104, small particle sizes, and molecular weights not exceeding 400 Da. Depending on the physicochemical properties of the drug molecule, the first systems of transdermal drug delivery are adequate for their therapeutic purposes but have a limited scope of application. Therefore, considerable efforts have been made to make more drug candidates available for transdermal application and improve their delivery efficiency.

2 First-generation transdermal drug delivery techniques by natural diffusion of the drug.webp

First-generation transdermal drug delivery techniques: by natural diffusion of the drug [1]

Second generation: non-invasive transdermal drug delivery with drive

Second-generation transdermal drug delivery strategies seek to maximize drug penetration into the skin using chemical enhancers or external energy sources without disrupting the skin structure. Chemical enhancers facilitate drug penetration through the skin by interacting with the proteins that make up the skin and increasing drug solubility. Milder chemical enhancers (e.g., fatty acids, urea, and pyrrolidone) may be used than skin irritants such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), and oxazolidinone. Emulsions are one of the main non-invasive transdermal drug delivery strategies because they dissolve many lipophilic and hydrophilic drugs in transdermal formulations. The absorption profile of emulsions is determined by droplet size, composition, and surface charge. In particular, reducing the size of carrier particles to the micron or nanometer level has been the more recommended strategy, as smaller droplets can easily penetrate the tight junctions of the skin barrier.

3 Second-generation transdermal drug delivery techniques drug delivery driven by external stimuli.webp

Second-generation transdermal drug delivery techniques: drug delivery driven by external stimuli [1]

Third-generation transdermal drug delivery technology: minimally invasive transdermal drug delivery

The limitations of non-invasive transdermal delivery have been recognized, so by the third generation, an alternative method of minimally invasive transdermal delivery has been adopted. Invasion of the skin involves only disruption of the stratum corneum, thus limiting epidermal disruption to a clinically safe level while delivering large amounts of hydrophilic drugs and macromolecules more efficiently to the inner layers of the skin. High-power energy modalities (e.g., radiofrequency, ultrasound, and laser) and various microneedles are currently used to pierce the skin and enhance drug delivery. However, skin disruption should be minimized and carefully controlled for rapid recovery.

4 Third generation enhanced drug delivery through microneedle-mediated skin layer disruption and various functions accompanying microneedles.webp

Third generation: enhanced drug delivery through microneedle-mediated skin layer disruption and various functions accompanying microneedles [1]

Fourth-generation transdermal drug delivery technology: controlled and feedback-induced transdermal drug delivery

Personalized treatment differs from conventional medical treatment in its ability to optimize treatment according to the pathophysiological condition of each individual. The establishment of personalized therapy requires systematic control of drug delivery doses based on accurate real-time observation of patient physiological parameters to determine disease progression and drug efficacy. In response to the growing need for personalized therapy, advanced transdermal drug delivery systems supported by software bioelectronics have emerged as a next-generation drug delivery methods strategy. The rapid development of ultra-thin wearable devices has facilitated the use of bioelectronic devices in skin patches. These "skin patches" contain sensors that accurately measure various physiological and biochemical signals, actuators that transmit energy to the drug-carrying patch in a controlled manner, and sensors that subsequently collect information about the drug treatment's efficacy. Based on a complete feedback loop, the synergistic performance of the wearable device and the drug delivery patch provides a new platform for personalized therapy.

5 Fourth-generation transdermal drug delivery technology for patient-tailored therapy with the help of wearable devices.webp

Fourth-generation transdermal drug delivery technology: for patient-tailored therapy with the help of wearable devices [1]

As demonstrated by first-, second-, and third-generation transdermal drug delivery strategies, research to overcome the skin barrier challenges to drug penetration and improve transdermal drug delivery efficiency has shown considerable success. Various approaches to improve drug delivery efficiency, from simple patches to complex microneedles, are still in progress. With the growing popularity of transdermal drug delivery, device-assisted transdermal drug delivery offers a new paradigm of drug delivery in response to real-time disease progression.

Transdermal Drug Delivery Market Outlook and Challenges

Transdermal drug delivery products will have ample market space in the future. They can avoid the gastrointestinal irritation and liver first-pass effect of the oral route of drug delivery and can maintain a constant and long-lasting effective blood concentration; they are easy to use. These advantages make transdermal drug delivery technology a popular means of developing new products, and therefore the future market space is enormous. In 2018, the essential products and services included basic research on process technology for new dosage forms of transdermal and mucosal drug delivery formulations. According to Research and Markets, the global transdermal drug delivery market is projected to exceed USD 90 billion by 2025. Given the more humane delivery characteristics of transdermal drug delivery and the continuous development of transdermal technology, it will have a broader prospect.

However, there are still some outstanding problems with transdermal formulations. The transdermal formulation industry is attacking new transdermal adjunct technologies to promote the transdermal ability of drug molecules and thus expand more drug types and indications, such as chemical and physical permeation promotion technologies. Chemical permeation promotion refers to the addition of other chemical components to enhance the penetration ability of drug molecules; physical permeation promotion refers to the use of external energy to change the nature of the skin barrier or increase the power of drug molecules, including ion introduction, ultrasonic method, electroporation, thermal perforation, microneedle, laser, and many other techniques.

Transdermal drug delivery characteristics

TDDS can achieve non-invasive drug delivery and has the following characteristics compared with conventional drugs:

Drug absorption is not affected by pH, food, transit time, etc., in the GI tract.

For topical application, the drug can be applied directly to the target site;

Avoid first-pass effects in the liver and interference from gastrointestinal factors;

Maintains a constant optimal blood concentration or physiological effect and reduces the side effects of gastrointestinal administration.

Maintain constant blood concentration for a long time, avoid peak and trough phenomenon, and reduce toxic side effects of drugs;

Prolong the adequate action time, reduce the number of doses, improve medication compliance, etc.

Reduced inter-individual variation, patient autonomy in dosing, ability to stop dosing at any time, flexible dosing, etc.

Examples of topical formulations

Although transdermal drug delivery has evolved from the first to the fourth generation, creams, ointments, and gels have been the most commonly used topical formulation dosage forms.

Based on consistent quality characteristics (viscosity, drug crystal, particle size, particle size distribution, droplet size, content and uniformity, relevant substances) of creams, ointments, and gels, the consistency of quality and efficacy of generic and reference formulations can be evaluated by in vitro release comparison and transdermal absorption comparison tests.

If the in vitro release and in vitro transdermal absorption are consistent, non-clinical studies and clinical trials may not be required.

If the pharmacological research is challenging to evaluate the quality consistency fully and there is a suitable pathological model, the corresponding non-clinical comparative study can be carried out.

If the above research still can not determine the bioequivalence of the generic drug and the reference formulation, it is recommended to carry out comparative clinical studies.

In vitro release (IVRT) and in vitro transdermal (IVPT) tests are currently essential tools for evaluating dosage forms and prescriptions of topical formulations (e.g., creams, ointments, gels, patches, applicators, etc.). Equipped with corresponding transdermal and testing instruments (LC-MS/MS), Medicilon can provide professional and efficient services in projects involving in vitro evaluation, such as compound screening, new drug declaration, pharmacological changes of marketed chemical drugs, consistency evaluation, and generic drug declaration.

Emulsions and emulsions are generally composed of oil and water phases and need to pay attention to the prescription differences with reference formulations. In principle, generic drugs should be selected with the same type of surfactant as the original product. Processes should analyze process conditions and the rationality of crucial process parameters and clarify the differences with the reference formulation process. For topical formulations in which the primary drug is in suspension, the main drug's particle size and size distribution should be controlled, and the consistency of the release behavior with the original product should be confirmed through in vitro dissolution studies.

The gel is a dosage form suitable for dermal, mucosal, and luminal administration, which is convenient for systemic or local therapeutic effects via dermal administration; and the excipients used are non-toxic and biodegradable, with good safety; it has obvious clinical advantages. In addition, it can achieve slow-release and controlled-release drug delivery by controlling the form of drug presence or adjusting the composition of the gel matrix.

Production process research, ointment, and gel need to pay attention to the raw material pretreatment process (micronization treatment), the way to join, and the dispersion means to study. We need to ensure that the generic drug and the reference formulation of drug crystallization, particle size and particle size distribution, content uniformity, and other key quality indicators of the same. The sequence of material addition, dissolution temperature, shear rate, and time need to be studied for creams and emulsions. Critical process parameters may significantly impact product quality, affecting the product's effectiveness.

Examples of topical formulations that Medicilon can cooperate to develop

Medicilon has concentrated on the research of Skin Topical Preparations for many years. Medicilon's Preparation Department is committed to providing clients with a one-stop and systematic preparation development service. It can undertake the process of preparation R&D innovation from project evaluation and approval, preparation process research, standard quality establishment, research, clinical sample production, application, filing, etc.

ProductsIntroduction
Tacrolimus ointmentIt is a non-hormonal anti-inflammatory topical drug. The main effect is anti-inflammatory, immunomodulation, etc., can release antihistamine, can effectively reduce the development of skin inflammation, and at the same time has a particular anti-itch effect.
Minoxidil tinctureA peripheral vasodilator that, when used topically for a long time, stimulates hair growth in patients with male pattern baldness and alopecia areata and is a hair growth promoter.
Progesterone Sustained-release vaginal gelIt's a progestin-like drug used as a supplemental treatment for progesterone in assisted reproductive technology. Progesterone Sustained-release vaginal gel is increasingly used in China for its ease of use and comfort, and the proportion of progesterone absorbed into the bloodstream by progesterone vaginal extended-release gel is small, thus reducing the risk of systemic side effects.

Summary and outlook

Transdermal drug delivery is a prospective delivery strategy that can compensate for the limitations of conventional delivery systems, including oral and injectable methods. Transdermal drug delivery is convenient and painless and has few side effects. However, physiological barriers in the skin disrupt the delivery efficiency of conventional patches, limiting drug candidates to small molecules and lipophilic drugs. The skin, long considered unsuitable for drug delivery, is now broadening the possibilities of drug delivery strategies with its physiological significance and convenience. More and more pharmaceutical companies are actively pursuing the development of transdermal drug delivery technologies, and it is believed that more new transdermal drug delivery systems will be introduced shortly.

Medicilon transdermal drug delivery service scope

Equipped with corresponding transdermal and testing instruments (LC-MS/MS), Medicilon can provide professional and efficient services in projects involving in vitro evaluation, such as compound screening, new drug declaration, pharmacological change of marketed chemical drugs, consistency evaluation, and generic drug declaration.

Service scope

Research and development of creams, ointments, gels, applications, patches, etc.

In vitro release and in vitro transdermal studies of topical formulations

Classic cases

Tacrolimus ointment, minoxidil tincture, Clindamycin Phosphate, Benzoyl Peroxide Gel, Progesterone Sustained-release vaginal gel, metronidazole vaginal gel, Triamcinolone Acetonide Acetate Cream, Neticonazole Hydrochloride Cream, etc.

Medicilon's Skin Topical Preparation R&D platform welcomes inquiries from pharmaceutical companies who need to collaborate with Medicilon to develop transdermal formulations. If you have any requests, please send an email to: Marketing@medicilon.com. We welcome your inquiry and communication~

References

[1] Hyunjae Lee, et al. Device-assisted transdermal drug delivery. Adv DrugDeliv Rev. 2018 Mar 1;127:35-45.

[2] Mark R Prausnitz, et al. Transdermal drug delivery. Nat Biotechnol.2008 Nov;26(11):1261-8.

[3] Muhammad Yasir Siddique, et al. Microemulsified Gel Formulations for Topical Delivery of Clotrimazole: Structural and In Vitro Evaluation. Langmuir. 2021 Nov 23;37(46):13767-13777.

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