Not to be underestimated! Eritative history of hydrogels and drug delivery

Hydrogels are composed of hydrophilic polymers, and their three-dimensional network structure can not only absorb a large amount of water, but also can be used to carry drugs Hydrogels prepared with suitable materials have the characteristics of
high biocompatibility, mechanical and viscoelastic controllability.
Since the invention of the term "hydrogel" at the end of the 19th century, hydrogels have been widely used in drug
delivery, wound dressing, tissue engineering, and hygiene products.
This article mainly introduces
hydrogels from the iterative history of hydrogels, the structural form of hydrogels and the application of drugs.

The term hydrogel dates back to 1894 and was first used to describe colloids
of some inorganic salts.
Time has passed, and the meaning of hydrogel has become completely different
from the beginning.
The world's first mature hydrogel product, Ivalon (a crosslink of formaldehyde ester and ethylene), came out in 1949, and PHEMA (polyhydroxyethyl methacrylate) came out in 1960 to prosper the hydrogel market, looking back at the history of hydrogels, which can be roughly divided into three generations
.

1 First generation hydrogels

The first generation of hydrogels is mainly divided into three categories, the first is a polymer of alkene monomer induced chain addition reaction by free radicals, mainly represented by polyacrylamide (PAM) and polyhydroxyethyl methacrylate (pHEMA).

Although it has been invented for more than 70 years, it is still an important biomaterial; The second class is covalently crosslinked hydrophilic polymers, mainly represented by polyvinyl alcohol (PVA) and polyethylene glycol (PEG), which are mainly used in tissue engineering; The third category is cellulose-based hydrogels, which are mainly used as drug dispersion matrices in the field of
drug delivery.

2 Second generation hydrogels

The second generation of hydrogels is mainly PEG/polyester block copolymer, compared with the first generation, the second stage is characterized by the ability to convert the chemical energy of the hydrogel into the mechanical energy of the hydrogel to achieve the specified function
.

In the 70s of the 20th century, this type of stimulus-responsive hydrogel appeared on the market, which can respond to
changes in the external environment, such as temperature or pH.
Stimulus-responsive hydrogels can be broadly divided into three categories:

The first type is temperature-sensitive hydrogels that respond to temperature, which can show phase transitions from gel state to sol state from low temperature to high temperature, mainly represented by BASF's Pluronics or Poloxamers of the British Imperial Chemical Industries Group;

The second major type of pH-sensitive hydrogel, these polymers are hydrolyzed at high or low pH, respectively;

The third is biomolecule-sensitive hydrogels, which can respond to
changes in concentration of specific biomolecules through conformational changes.
Such as glucose oxidase hydrogels, this hydrogel can be used for insulin delivery
.
The basic principle is: when glucose diffuses in the hydrogel matrix, it will be converted into gluconic acid by glucose oxidase in the hydrogel, which will lead to a decrease in the pH of the environment, and the increase in swelling caused by the protonation of the amine functional group of the hydrogel allows insulin to be released from the matrix, forming a system
of insulin self-regulating release.

3 Third generation hydrogels

The main feature of the third generation of hydrogels is "crosslinking", which mainly adjusts the mechanical properties and degradation properties
of hydrogels through stereo complexation, clathrates, metal-ligand coordination and synthetic peptide chains 。 For example, one of the main applications of the stereo complexation method is the preparation of injectable hydrogels by blocking two amphiphilic copolymers, PLLA (polylactic acid) and PDLA (polylactic acid enantiomer); There are also studies on the construction of hydrogels with hydrophobic cavities that can accommodate different molecules using cyclodextrin complexes, and in genetic engineering, there are also studies of synthetic peptide (or protein) hydrogels constructed using the folded structure of peptides, but such hydrogels are mainly reflected in research
.

The unique hydrophilic, three-dimensional structure of hydrogels makes molecules and cells diffuse and attach properties, through different crosslinking methods, so that the hydrogel has temperature, concentration or external environment stimulus response, and finally these properties can be widely used in drug delivery, so that hydrogel plays an important role
as a drug carrier.
In this paragraph, drugs
based on hydrogel delivery are mainly introduced.

1 Oral administration

Oral administration of hydrogel is characterized by ease of administration, good patient compliance, rapid onset of action, easy removal, low risk of irritation or adverse side effects, and can avoid drug degradation and first-pass effects
in the gastrointestinal tract.

The main multi-layer epithelium of the oral cavity, according to the physiological structure can be roughly divided into the bottom of the mouth, the inside of the cheeks and the gums, the delivery process of drugs in the oral cavity mainly through: drug dissolution, drug passive or active way through the mucosa diffusion to the local blood circulation system, and finally and reach the whole body blood circulation process, so the permeability of different parts brings different ways
of administration.

The sublingual mucosa is more permeable than the buccal mucosa and is suitable for drugs that require rapid onset, but sublingual mucosal administration can affect tongue movement
during speech.
In contrast, buccal administration on the mucosa has little effect on tongue activity, preferably for the treatment of chronic diseases, and gum delivery of drugs is often limited to local action
.
A large part of mucosal administration goes to the gastrointestinal tract, so the design of the dosage form considers adhesive hydrogels
.
Hydrogel-based bioadhesive tablets can be used by hydration to control the rate of drug release
.
Commonly used matrices in these hydrogel applications are: hydroxypropyl cellulose (HPC), hydroxyethylcellulose (HEC), polyacrylic acid (PA) resin, carboxymethylcellulose (CMC), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), chitosan, etc
.

Hydrogel pharmaceuticals currently on the market, which range from hydrogels for oral care and hydration to continuous drug delivery systems for the prevention of angina, are listed
in the table below.

2 Vaginal administration

Bacteria, fungi or viruses can easily multiply in the vaginal cavity, causing a variety of lesions and inducing vaginitis, and the vagina has traditionally been used as a route
of administration for the delivery of antimicrobial and antiviral drugs.
In addition, vaginal administration is an alternative
to parenteral routes of administration of propranolol, human growth hormone, insulin, and steroids due to its large surface area, high perfusion of tissues, and high permeability, including peptides and proteins.
The main obstacle to vaginal administration is a change in vaginal fluid content and permeability of the vaginal mucosa caused by changes in age and hormone levels, which in turn affects the release of the drug and changes
in pharmacokinetics.

There are currently two main approaches to overcome this limitation: the use of mucosal adhesions to prolong the residence time of the drug on the vaginal mucosa, and the use of stimulus-sensitive hydrogels
with sol-gel transitions in the vaginal environment.
Both solutions rely primarily on matrix excipients
.
The most commonly used polymers in vaginal preparations are hydrogels: polyacrylates, chitosan, cellulose derivatives such as carboxymethylcellulose (CMC), hydroxypropyl methylcellulose (HPMC), hyaluronic acid, alginate and gelatin
.
The main drugs currently on the market, their range is mainly care products and gynecological drugs, are listed
in the table below.

3 Percutaneous administration

Transdermal administration is a special mode of administration suitable for oral drugs with poor absorption, high first-pass effect and patients
who cannot tolerate injection.
The skin is an uneven membrane characterized by very low penetration, which reduces water loss and stops toxins from flowing into the body
.

The outermost layer of the skin is the stratum corneum, although it is only 20~25 μm thick, which can prevent the penetration of foreign substances, but it is also the biggest obstacle
to percutaneous administration.
Routine transdermal patch administration requires drugs with low molecular weight, high lipophilicity, and small
doses.
In 1979, the United States approved the first transdermal system for systemic administration, scopolamine transdermal patch
.
Ten years later, the nicotine patch was launched, as a heavyweight transdermal preparation, the nicotine patch not only has the characteristics of high patient compliance, but also greatly improves the popularity
of transdermal preparations in patients.

The conventional transdermal patches marketed in recent years can be divided into two categories: storage patches and matrix patches
.
The first features keep the drug in a solution or gel, controlling the delivery
of the drug through a membrane located between the drug reservoir and the skin.
The latter combines the adhesion and mechanical properties of the formulation, and the drug delivery rate is controlled
only by skin permeability.
Therefore, overcoming the permeability of the skin is the key to the problem, and the hydrogel promotes the skin penetration of the drug through skin hydration through moisturizing, and exerts local and systemic effects
.
Listed below are some of the commercial products on the market based on transdermal delivery hydrogels that cover a relatively wide range of products, from dermatology to systemic administration
.

4 Ocular administration

The eye is a very special organ because it contains several different structures, each with a specific function
.
For this reason, ocular drug delivery has always been a difficult task
.
Ocular drug delivery, the first problem to solve is the loss of drugs from the ocular surface, mainly due to the flow of tears, which will dilute the drug and affect the absorption of the drug, in addition to the presence of the corneal barrier, the blood-eye barrier, these obstructions will lose about 95% of the administered dose, so the ideal characteristics of the ophthalmic drug delivery system are: prolonged contact time with the cornea, appropriate rheology, easy to administer
to the patient.

With the rational formulation design of the hydrogel, it is possible to prolong the contact time, especially with subconjunctival administration, the drug can bypass the conjunctiva-corneal barrier, directly enter the transscleral route, and enter the back of the
eye.
Hydrogel preparations already have a variety of ophthalmic applications because they offer several advantages over traditional materials, such as mild preparation conditions, high water content, important characteristics
of maintaining molecular activity such as proteins.
Moreover, certain temperature-sensitive and in situ hydrogel types of hydrogels can achieve long-term implantation administration in a less invasive way
.
Some of the commercial products
for hydrogel-based eye delivery on the market are listed below.

Although hydrogels have been around for more than half a century, their charm remains unquestionable
.
Due to its unique properties, hydrogels have always attracted the attention of the pharmaceutical industry, although relevant theoretical studies have been deeply excavated into it, but there are still many prescriptions that have not entered the market, and hydrogels are still promising in the field of drug delivery
.
This article mainly summarizes the iterative history and some application scenarios of hydrogels, and briefly shows the related marketed drugs
.

The pharmaceutical market not only has first-in-class drugs, but also many dosage forms and processes, and the gap between us and international pharmaceutical giants is not only reflected in new drugs, but also in the gap
in preparation processes.
China's pharmaceutical industry has long been in the development mode of "heavy APIs and light preparations", and the level of drug generic preparations is low and it is facing the dilemma
of not being able to pass the consistency evaluation.
As the final product of the pharmaceutical industry industry chain, pharmaceutical preparations are the only way for the transformation and development of the domestic pharmaceutical industry, and I hope to pay more attention to this field, improve the domestic pharmaceutical level in all aspects, and hope that the dosage form of hydrogel can have greater development
in the field of drug delivery.

Key references

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Hydrogels: From simple networks to smart materials—advances and applications - ScienceDirect[J].
Drug Targeting and Stimuli Sensitive Drug Delivery Systems, 2018:627-672.

[2] Prausnitz M R, Mitragotri S, Langer R.
Current status and future potential of transdermal drug delivery[J].
Nature Reviews Drug Discovery, 2004,3(2):115.

[3] Cascone S, Lamberti G.
Hydrogel-based commercial products for biomedical applications: A review[J].
International Journal of Pharmaceutics, 2019,573:118803.

[4] Bertens, Christian, J.
, et al.
Topical drug delivery devices: A review[J].
Experimental Eye Research, 2018.

[5] Caló E, Khutoryanskiy V V.
Biomedical applications of hydrogels: A review of patents and commercial products - ScienceDirect[J].
European Polymer Journal, 2015,65:252-267.