Application research progress of implantable drug delivery system

Oral and injection are currently the most common and popular routes of administration, but for some drugs, there are problems such as low bioavailability, short half-life, and repeated medications.
Therefore, it is necessary to research and develop other drug delivery systems to improve The curative effect of the medicine makes it safer and more reliable
.
Implantable drug delivery system is a kind of controlled release system that is surgically implanted or introduced into the subcutaneous or target site through a special device.
It can achieve local or systemic drug delivery, reduce dosage and reduce side effects, and can also avoid first-pass effects and The gastrointestinal tract is degraded and the bioavailability is improved.
In addition, its high drug loading and small size can prolong the action time of the drug.
It is especially suitable for the long-term treatment of chronic and senile diseases and improves patient compliance
.

Implantation preparation is a special kind of sustained and controlled release preparation.
Due to the complex production process and high technical requirements, there are not many products on the market.
However, with the development and application of new technologies in recent years, implant preparations have received extensive attention and in-depth research.
The scope of drug application has also expanded from the original reproductive health to various therapeutic fields such as tumor treatment, eye diseases, insulin administration, and cardiovascular diseases
.

01 Classification of implantable drug delivery systems

According to the difference between the way the drug exists in the implant and the way the implant is used, it can be divided into solid drug-carrying implants, injection-administered implants, and implant pump formulations
.

Solid drug-loaded implant

Refers to a drug is dispersed in a carrier material, in the form of columns, rods, pellets, sheets, etc.
administration by surgical implantation
.
According to different carrier materials, it can be divided into non-biodegradable type and biodegradable type
.

Non-biodegradable implants are one of the early research and application implant systems.
They are made of carrier materials that are not biodegradable in the body through a certain preparation method.
Commonly used materials are silicone rubber, polyurethane, polyacrylate, and polyvinyl acid.
vinyl acetate copolymers and the like
.
Norplant is the most well-known implanted subcutaneous capsule for long-acting contraception in the clinic.
This product contains 6 small silicone rubber capsules, each with 36mg levonorgestrel, which is implanted under the skin of the inner upper arm of a woman.
The contraceptive cycle is long It has been widely used in many countries since it was approved for marketing by the US FDA in 1990 for 5 years
.
However, the non-biodegradable implanted drug delivery system needs to be collected and removed by surgery after the drug release cycle ends.
This process often causes discomfort and secondary injury to the patient's body
.

The biodegradable carrier material can be spontaneously degraded into monomer small molecules in the body.
The degradation mechanism includes hydrolysis, enzymatic hydrolysis, oxidation, physical degradation and other processes.
After the release of the drug, it does not need to be removed by surgery, which greatly improves the patient Compliance
.
Such materials have partially replaced non-biodegradable materials for the production of contraceptives and anti-tumor drug implants.
For example, the implant Gliadel Wafers was used in the chemotherapy of postoperative brain tumors in 2000, and other impenetrable Blood-brain barrier anti-tumor drugs (such as carboplatin, cyclophosphamide) are directly implanted into the brain for treatment
.

Implants for injection administration

Implants for injection administration are the injection of polymer materials into the human body to cause the polymer to produce a reversible change in the dispersion state or conformation under physiological conditions, so that the injection is transformed from liquid to gel, forming a semi-solid drug library, and passing through it.
The degradation process stably controls the release of the drug for a long time
.
Compared with a conventional preformed implants, the dosage form having a relatively simple production, less damage to the body, and good patient compliance, can be used for systemic and local drug delivery, tissue engineering, plastic surgery and the like
.

According to the mechanism of in vivo formation, it can be roughly divided into in vivo crosslinking systems, in vivo curing organogels, solvent removal precipitation systems and other types
.

The in-body cross-linking system is to cross-link the implants in the body to form a polymer network solid or gel through heating, light, ion-mediated methods and other methods
.
This system has strict requirements on the reaction conditions in the body, and a certain amount of heat is usually released when the chemical cross-linking reaction occurs, causing damage to the body tissues, while the physical cross-linking system has higher requirements on the conformation of the polymer itself
.

In vivo solidified organogels are composed of amphoteric lipid molecules that are insoluble in water.
Most of these lipids are glycerol oleate.
The solution is injected into the body's water environment and the lipid swells to form a three-dimensional lipid bilayer.
In the cubic liquid crystal phase, the bilayers are separated by water channels
.
The liquid crystal phase has a high viscosity and a gel-like structure, which can be used for controlled drug release
.
At present, this type of system is mainly used for controlled-release lipophilic drugs, and the preparation process of organogel is relatively complicated and has many influencing factors, which limits the in-depth study of this system
.

The solvent removal precipitation system uses the principle of phase separation to dissolve the water-insoluble polymer in a water-miscible organic solvent and then inject it into the body.
The organic solvent diffuses into the surrounding body fluid environment, and at the same time the surrounding water molecules diffuse into the polymer to solidify it.
Precipitation at the injection site forms a drug depot
.
Therefore, the main disadvantage of this system is that the burst release at the initial stage of implantation is relatively large, and the organic solvent has certain toxicity
.
At present, the products of this system have been approved by the US FDA.
The representative product is the Eligard series launched by Atrix Laboratories in 2002.
This series is a suspension of leuprolide acetate for subcutaneous injection, which can release 1, 3, 4 , 6 months, used for palliative treatment of advanced prostate cancer
.

Implant pump preparation

Implantable pumps are implants with micro-pumps.
By implanting a pump or a catheter into the site of action, the drug is slowly injected by itself or the external environment
.
Compared with the non-degradable/degradable implant system, the drug release rate is more stable (generally up to zero-level release), and the drug delivery rate can be adjusted more accurately according to clinical needs; the power source can be used for a long time and can be injected subcutaneously Replenishing the liquid medicine into the pump in equal ways avoids multiple injections; however, the cost is generally high, and some devices are externally attached, which affects patient compliance
.

According to the different power released, it can be divided into: infusion pump, peristaltic pump, osmotic pump and so on
.
Infusion pumps use fluorocarbons as the driving force and are widely used in the treatment of diabetes for insulin administration.
The first product to apply this principle is the Infusaid implantable pump from Metal Bellows in the United States; the peristaltic pump is made of spiral type conduct The power of the electric field to operate the peristaltic pump has the advantage that the drug release can be adjusted by changing the strength of the external electric field
.
The Synchromed developed by Medtronic is a fully implantable peristaltic pump; the osmotic pump is made of a polymer material to form a shell, and the inside is divided into two compartments by a freely movable diaphragm, which are respectively filled with pharmaceutical preparations and penetrants
.
The water molecules in the tissue enter the penetrant chamber, dissolve the penetrant, increase the osmotic pressure, and push the diaphragm in the middle to press out the drug solution in the other chamber from the drug guide hole
.
Viadur is a typical product that applies this principle and is used to release leuprolide acetate to treat prostate cancer
.

02 Clinical application of implantable drug delivery system

Reproductive health

Norplant is a subcutaneous contraceptive implant developed by the US Population Council.
The effect can be maintained for 5 years
.
Norplant is convenient to use as its most prominent advantage.
It is not necessary to seek medical attention frequently after placement, local special care is not required, and contraception is highly effective and has high acceptability
.
Up to now, the US FDA clearance to market implantable products, including Vantas, Retisert, Nexplanon, SupprelinLA, Iluvien, Probuphine, NuvaRing and so on
.

tumor treatment

Oral chemotherapy drugs are the most commonly used route of administration for the treatment of tumors, but large doses of drugs often lead to serious systemic side effects
.
By directly implanting the drug delivery device into the site of action, the drug dose can be greatly reduced, thereby reducing damage to other healthy tissues
.
The carmustine anti-tumor implant Gliadel developed by Guilford was used in the chemotherapy of malignant glioma in 2000, allowing the direct implantation of anti-tumor drugs (carboplatin, cyclophosphamide) that cannot penetrate the blood-brain barrier Chemotherapy is performed intracranially
.
Alza has developed a sustained-release gel Lupron DUROS, which is protected and fixed by a small titanium implant.
The drug can last for 12 months and is used to treat advanced prostate cancer
.
At present, the implantable sustained-release dosage forms of anti-cancer chemotherapy drugs cisplatin, fluorouracil and methotrexate have been developed in China
.

Eye diseases

For the treatment of diseases of the posterior segment of the eye, it is difficult for conventional preparations to effectively penetrate the cornea and enter the lesion to achieve the therapeutic effect.
The ocular implants target the posterior segment of the eye to increase the local drug concentration and release the drug slowly to improve patient compliance.
Sex
.

In 1996, the first ocular implant approved by the FDA to be marketed was a non-biodegradable implant containing ganciclovir (trade name Vitrasert), which was used to treat cytomegalovirus retinitis in AIDS patients with a long sustained release time.
Up to 8 months
.
The only biodegradable ocular implant approved by the FDA at present is the dexamethasone intravitreal implant (trade name Ozurdex) developed by Allergan of the United States.
It has a rod-shaped appearance and a size of 6.
5mm×0.
45mm.
The 22-G needle is injected into the vitreous cavity through the flat part of the ciliary body, and the sustained release time of dexamethasone is about 6 months.
It is used to treat retinal vein occlusion and macular edema secondary to diabetic retinopathy
.
In 2005, SFDA approved the listing of dexamethasone implants (Sino Diqing) developed by Beijing Zizhu Pharmaceutical Co.
, Ltd.
, which are white or off-white cylindrical particles for use in the eye caused by cataract extraction and implantation of intraocular lenses.
Meningitis, the drug can be released continuously for 7 days
.

Diabetes treatment

The insulin implant pump is an implant with a micro-pump, which can automatically and slowly inject drugs at a designed rate to obtain a controllable drug release rate
.
According to the degree of automatic control of the insulin pump, it is divided into an open-loop pump and a closed-loop pump
.
The open-loop pump cannot automatically monitor the blood glucose concentration.
The patient continuously injects a certain amount of insulin into the body according to the blood glucose level, and adjusts and increases the input dose before meals to mimic the increase in secretion after meals and the increase in plasma insulin
.
The insulin pumps currently on the market are all open-loop pumps
.
The closed-loop insulin pump implanted in the body is mainly composed of a blood glucose sensor that can continuously monitor blood glucose, a microcomputer, and an insulin injection pump, which can automatically adjust the amount of insulin injection according to changes in blood glucose concentration
.
The titanium pump is surgically placed on the patient's abdominal subcutaneous fat area.
The battery life is 7 to 10 years, and transdermal puncture is required to replenish insulin every 6 to 8 weeks
.

Although implant preparations have a series of advantages over traditional administration methods such as oral and intravenous injection, there are still some problems
.
First of all, the drug delivery method implanted in the body itself will cause some physical discomfort and poor biocompatibility to the patient.
Therefore, it is necessary to continuously improve the implanted device to make it more compact and gentle, reduce the harm to the human body, and improve the patient's compliance.
Sex
.
Secondly, implants need to achieve slow release of drugs at specific locations and at specific speeds over a long period of time.
This usually requires very complex and sophisticated system design, which increases the difficulty of research and development costs, so how to obtain them at the lowest cost The most effective drug delivery system is another major problem in the development of implants
.
( CPhI Pharma Online )

references:

[1] Yu Kunmeng, Ping Qineng, Sun Minyi.
The application and development trend of implantable drug delivery systems [J].
Progress in Pharmaceutical Sciences, 2020, 44(05): 361-370.

[2] Lin Xiaoming, Guo Ningzi, Yang Huaxin, Liu Yang, Liu Wanhui.
Research progress in quality control of implantable preparations[J].
Chinese Journal of New Drugs, 2019, 28(05): 528-535.