Pharmaceutical Sustained-release Excipients

01 Cellulose ether

Cellulose can be divided into single ethers and mixed ethers according to the type of substituents. There is only one type of substituent in a single ether, such as methyl cellulose (MC), ethyl cellulose (EC), hydroxyl Propyl cellulose (HPC), etc.; there can be two or more substituents in the mixed ether, commonly used are hydroxypropyl methyl cellulose (HPMC), ethyl methyl cellulose (EMC), etc. . The excipients used in pulse-release drug preparations are represented by mixed ether HPMC, single ether HPC, and EC, which are often used as disintegrants, swelling agents, retarders, and film coating materials.

1.1 Hydroxypropylmethylcellulose (HPMC)

Due to the different degrees of substitution of methoxy and hydroxypropyl groups, HPMC is generally divided into three types abroad: K, E and F. Among them, the K series has the fastest hydration speed and is suitable as a skeleton material for sustained and controlled release preparations. It is also a pulse release agent. One of the most commonly used drug carriers in pharmaceutical preparations. HPMC is a water-soluble non-ionic cellulose ether, white powder, tasteless, odorless and non-toxic, and it is excreted without any change in the human body. It is basically insoluble in hot water above 60°C and can only swell; when its derivatives with different viscosities are mixed in different proportions, the linear relationship is good, and the formed gel can effectively control water diffusion and drug release.

HPMC is one of the commonly used polymer materials based on swelling or erosion controlled drug release mechanism in pulse release system. Swelling drug release is to prepare active pharmaceutical ingredients into tablets or pellets, and then multi-layer coating, the outer layer is Water-insoluble but water-permeable polymer coating, the inner layer is a polymer with swelling ability, when the liquid penetrates into the inner layer, swelling will generate pressure, and after a period of time, the drug will be swollen and controlled to release the drug; while the erosion release drug is through the core drug package. Coating with water-insoluble or erosion polymers, adjusting the coating thickness to control drug release time.

Some researchers have investigated the release and expansion characteristics of tablets based on hydrophilic HPMC, and found that the release rate is 5 times slower than that of ordinary tablets and has considerable expansion.

Still have researcher to use pseudoephedrine hydrochloride as model medicine, adopt dry coating method, prepare coat layer with HPMC of different viscosities, adjust the release of medicine. The results of in vivo experiments showed that under the same thickness, low-viscosity HPMC could reach the peak concentration in 5h, while high-viscosity HPMC reached the peak concentration in about 10h. This suggests that when HPMC is used as a coating material, its viscosity has a more significant effect on drug release behavior.

The researchers used verapamil hydrochloride as a model drug to prepare double-pulse three-layer tablet core cup tablets, and investigated different dosages of HPMC K4M (15%, 20%, 25%, 30%, 35%, w/w; 4M refers to the effect of viscosity (4000 centipoise) on the time lag. The results show that with the increase of the amount of HPMC K4M, the time lag is prolonged. The time lag is set at 4 to 5 hours, so the HPMC K4M content is determined to be 25%. This shows that HPMC can delay the release of the core drug by preventing the drug from contacting with the liquid and play a role in controlled release.

1.2 Hydroxypropylcellulose (HPC)

HPC can be divided into low-substituted hydroxypropyl cellulose (L-HPC) and high-substituted hydroxypropyl cellulose (H-HPC). L-HPC is non-ionic, white or off-white powder, odorless and tasteless, and is medium Non-toxic cellulose derivatives that are harmless to the human body. Because L-HPC has a large surface area and porosity, it can quickly absorb water and swell, and its water absorption expansion rate is 500-700%. Penetrate into the blood, so it can promote the release of the drug in the multi-layer tablet and pellet core, and greatly improve the curative effect.

In tablets or pellets, adding L-HPC helps the tablet core (or pellet core) to expand to generate internal force, which breaks the coating layer and releases the drug in a pulse. The researchers used sulpiride hydrochloride, metoclopramide hydrochloride, diclofenac sodium, and nilvadipine as model drugs, and low-substituted hydroxypropyl cellulose (L-HPC) as the disintegrating agent. The experiments showed that the thickness of the swelling layer determines the particle size. lag time.

The researchers used antihypertensive drugs as the study object. In the experiment, L-HPC was present in the tablets and capsules, so that they absorb water and then erode to release the drug quickly.

The researchers used terbutaline sulfate pellets as a model drug, and the preliminary test results showed that using L-HPC as the material of the inner coating layer and adding appropriate SDS to the inner coating layer can achieve the expected pulse release effect.

1.3 Ethyl cellulose (EC) and its aqueous dispersion (ECD)

EC is a non-ionic, water-insoluble cellulose alkyl ether, which has the characteristics of chemical resistance, salt resistance, alkali resistance and heat stability, and has a wide range of viscosity (molecular weight) and good clothing performance , can form a coating layer with good toughness and is not easy to wear, which makes it widely used in drug sustained and controlled release film coating.

ECD is a heterogeneous system in which ethyl cellulose is suspended in a dispersant (water) in the form of tiny colloidal particles and has good physical stability. A water-soluble polymer that acts as a pore-forming agent is used to adjust the release rate of the ECD to meet the requirements of sustained drug release for sustained-release preparations.

EC is an ideal material for the preparation of non-water-soluble capsules. The researchers used dichloromethane/absolute ethanol/ethyl acetate (4/0.8/0.2) as solvent and EC (45cp) to prepare 11.5% (w/v) EC solution , prepare the EC capsule body, and prepare the non-permeable EC capsule meeting the requirements of oral pulse release. The researchers used theophylline as a model drug to study the development of a multiphase pulse system coated with ethyl cellulose aqueous dispersion. The results showed that the Aquacoat® variety in ECD was fragile and easy to break, ensuring that the drug could be released in a pulse.

In addition, the researchers studied the pulse-controlled release pellets prepared with ethyl cellulose aqueous dispersion as the outer coating layer. When the weight gain of the outer coating layer was 13%, the cumulative drug release was achieved with a time lag of 5 h and a time lag of 1.5 h. More than 80% of the pulse release effect.

02 Acrylic resin

Acrylic resin is a kind of polymer compound formed by copolymerization of acrylic acid and methacrylic acid or their esters in a certain proportion. The commonly used acrylic resin is Eudragit as its trade name, which has good film-forming properties and has various types such as gastric-soluble E type, enteric-soluble L, S type, and water-insoluble RL and RS. Because Eudragit has the advantages of excellent film-forming performance and good compatibility among various models, it has been widely used in film coating, matrix preparations, microspheres and other pulse release systems.

The researchers used nitrendipine as a model drug and Eudragit E-100 as an important excipient to prepare pH-sensitive pellets, and evaluated their bioavailability in healthy dogs. The results of the study found that the three-dimensional structure of Eudragit E-100 enables it to be released rapidly within 30 minutes under acidic conditions. When the pellets are at pH 1.2, the time lag is 2 hours, at pH 6.4, the time lag is 2 hours, and at pH 7.8, the time lag is 3 hours, which can realize controlled release administration in the intestinal tract.

The researchers carried out the ratios of 9:1, 8:2, 7:3 and 6:4 on the film-forming materials Eudragit RS and Eudragit RL respectively, and found that the time lag was 10h when the ratio was 9:1, and the time lag was 10h when the ratio was 8:2. The time lag is 7h at 2, the time lag at 7:3 is 5h, and the time lag at 6:4 is 2h; for porogens Eudragit L100 and Eudragit S100, Eudragit L100 can achieve the pulse purpose of 5h time lag in the pH5-7 environment; 20%, 40% and 50% of the coating solution, it was found that the coating solution containing 40% EudragitL100 can meet the time lag requirement; the above conditions can achieve the purpose of a time lag of 5.1 h at pH 6.5 and a pulse release time of 3 hours .

03 Polyvinylpyrrolidones (PVP)

PVP is a non-ionic water-soluble polymer compound polymerized from N-vinylpyrrolidone (NVP). It is divided into four grades according to its average molecular weight. It is usually expressed by K value. The greater the viscosity, the stronger the adhesion. PVP gel (powder) has a strong adsorption effect on most drugs. After entering the stomach or blood, due to its extremely high swelling property, the drug is released slowly. It can be used as an excellent sustained release agent in PDDS.

Verapamil pulse osmotic tablet is a three-layer tablet osmotic pump, the inner layer is made of hydrophilic polymer PVP as the push layer, and the hydrophilic substance forms a hydrophilic gel when it meets water, which retards drug release, obtains time lag, and pushes The layer swells strongly when it encounters water, pushing the drug out of the release hole, and the osmotic pressure propellant is the key to the success of the formulation.

The researchers used verapamil hydrochloride controlled-release tablets as model drugs, and used PVP S630 and PVP K90 with different viscosities as controlled-release coating materials. When the film weight gain is 8%, the time lag (tlag) to reach in vitro release is 3-4 hours, and the average release rate (Rt) is 20-26 mg/h.

04 Hydrogel

4.1. Alginic acid

Alginic acid is white or light yellow powder, odorless and tasteless, a natural cellulose insoluble in water. The mild sol-gel process and good biocompatibility of alginic acid are suitable for making microcapsules that release or embed drugs, proteins and cells – a new dosage form in PDDS in recent years.

The researchers used dextran as a model drug and calcium alginate gel as a drug carrier to make a pulse preparation. Results The drug with high molecular weight exhibited time-lag-pulse release, and the time lag could be adjusted by the thickness of the coating film.

The researchers used sodium alginate-chitosan to form microcapsules through electrostatic interaction. Experiments show that the microcapsules have good pH responsiveness, zero-order release at pH=12, and pulse release at pH=6.8. The release curve Form S, can be used as a pH-responsive pulsatile formulation.

4.2. Polyacrylamide (PAM) and its derivatives

PAM and its derivatives are water-soluble high molecular polymers, which are mainly used in the pulse release system. The heat-sensitive hydrogel can reversibly expand and de-expand (shrink) with the change of external temperature, causing a change in permeability, thereby To achieve the purpose of controlling drug release.

The most studied is N-isopropylacrylamide (NIPAAm) hydrogel, with a critical melting point (LCST) of 32°C. When the temperature is higher than the LCST, the gel shrinks, and the solvent in the network structure is squeezed out, releasing a large amount of Drug-containing aqueous solution; when the temperature is lower than LCST, the gel can re-swell, and the temperature sensitivity of NPAAm gel can be used to adjust the swelling behavior, gel size, shape, etc. to achieve precise “on-off” drug release temperature and Drug release rate thermosensitive hydrogel pulsatile controlled release formulation.

The researchers used a composite of temperature-sensitive hydrogel (N-isopropylacrylamide) and superferric iron tetroxide particles as a material. The network structure of the hydrogel is changed, thereby accelerating the drug release and obtaining the effect of pulse release.

05 other categories

In addition to the widespread use of traditional polymer materials such as HPMC, CMS-Na, PVP, Eudragit, and Surlease, other new carrier materials such as light, electricity, magnetic fields, ultrasonic waves, and nanofibers have been continuously developed. For example, the sonic-sensitive liposome is used as a drug carrier by researchers, and the addition of ultrasonic waves can make a small amount of gas in the sonic-sensitive liposome move, so that the drug can be released quickly. The electrospun nanofibers were used by the researchers in TPPS and ChroB to design a four-layer structure model, and the pulse release could be realized in the simulated in vivo environment containing 500μg/ml protease, 50mM hydrochloric acid, pH8.6.