Jalor filler production is subdivided into 2 stages:

1. Preparation to the stabilization of Multi Chain Matrix
   Preparation of HA (Hyaluronic acid) for the reaction. Based on the technology, HA enters the homogenizer, wherein at the elevated temperature and under high mixing intensities a reactive mixture of HA is being created. HA molecules are evenly distributed throughout the solution;

Then the resulting HA solution enters the reactor, where the mixture is pressurized to several atmospheres with nitrogen to open the HA molecules;

As a result of the preparatory phase, the following two critical processes occur:

• All necessary reaction centers are liberated, namely the hydroxyl groups (-CH2OH), since when BDDE is attached to the carbonyl groups, some “inefficient” crosslinks are being formed.
• The polymer matrix formed later is quite streamlined due to the preliminary homogenization and similar size of HA molecules (3 million Da [daltons]).

Fig.1 SEM photo (taken using the scanning electron microscope) in section – HA matrices with the same degree of crosslinking

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(A) – HA molecules in a matrix of different sizes; (B) – HA molecules of the same size

Stage effects:

a) Elevated uniformity of the drug biodegradability in the body due to low porosity of the formed matrix after the reaction with BDDE

b) Almost all HA molecules are involved in subsequent reaction with BDDE, and those that have not reacted will be removed easily at the purification stage. The absence of native (unreacted) HA in the final product affects cohesiveness of the filler positively.

2. The stabilization process using Multi Chain Matrix technology can be conditionally subdivided into 3 stages:

1) To the reactor, where the HA solution is present, under vigorous stirring and at elevated temperature, BDDE is added portionwise, herein the first crosslinking of HA takes place. The resulting complexes represent the intermediate product (i – MCM complexes) being the streamlined compositions of crosslinked HA of small size;

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The reaction conditions and the concentrations of reacting substances (MCM) are selected in such a way that the HA stabilization reaction proceeds strictly according to the mechanism of attaching one BDDE molecule to two hydroxyl groups of different HA molecules. In this case, a “suspended” BDDE is not generated; it affects both the drug cohesiveness and its biodegradation period in a negative way.

2) After the reaction, the intermediate product enters the tank, wherein it is cleaned off the residues of native HA and unbound BDDE, after which the mixture enters the reactor again;

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3) A second portion of BDDE is fed into the cleaned intermediate product present in the reactor to crosslink the compositions formed during the first stabilization stage.
BDDE is added to the reactor portionwise with constant stirring of medium intensity. The resulting final product (MCM) is a linearly crosslinked MCM complex that forms a streamlined matrix that does not contain any native HA within its structure.

As a result of this HA stabilization using MCM technology:

• high cohesiveness is achieved due to the fact that 100% of HA molecules are crosslinked in the preparation
• the duration and uniformity of biodegradation of the drug in the body is expanded
• structure of the resulting preparation allows moisture and nutrients to freely penetrate into the tissues of the body, but prevents the penetration of HA cleavage enzymes into its structure as they are quite bulky;
• due to the fact that the degree of crosslinking of HA molecules with each other is low, the optimum viscosity is achieved, which allows the drug to be injected into the body using small-diameter needles with no effort.
• the absence of native HA has the following positive outcomes:
• – cohesiveness of the drug;
• – expand the duration and uniformity of biodegradation.

Native HA is disintegrated in the body by hyaluronidase enzyme much faster than its cross-linked analogues. If fragments of native HA are included into the matrix, they will be split first, forming some “foci of cleavage,” resulting in expanded area of possible attack at the HA matrix with hyaluronidase, decreasing the biodegradation period of the drug. Cleavage reactions will also occur in larger quantities specifically in these foci, rather than on the remaining surface of the filler, which will negatively affect the uniformity of biodegradation of the drug in the body.     

Due to the ABSOLUTELY UNIQUE technique for crosslinking HA, Jalor is a product having optimum viscosity for injection with very high cohesiveness, and it is also characterized by long biodegradation period in the body.        

• Purification and homogenization of the final product.

1. Deep purification of the drug from proteins, endotoxins and residual BDDE.

At this stage, the sequential in-depth purification of the drug from proteins, endotoxins and residues of unreacted BDDE occurs, which makes the drug absolutely safe for use.

• – the drug does not cause any allergic reactions and irritation during injection;
• – BDDE (Fig. 5) is a very toxic substance; its concentration should not exceed 2 ppm (0.0002%), therefore, complete purification of the filler from this substance will positively impact the clients’ health.

1,4-budanediol-diglycidyl ether (BDDE)

2. Homogenization of the final product

After the reaction and purification, the drug is a heterogeneous mass unsuitable for injections. Therefore prior to packing, the product enters a sterile homogenizer, where, at elevated temperature and under vigorous stirring, the Jalor filler acquires its final look. Homogenization of the final product before packing makes the Jalor filler uniform and of homogeneous viscosity.

HA stabilization using BDDE (Fig. 3)

The reaction conditions and the concentrations of reacting substances (MCM) are selected in such a way that the HA stabilization reaction proceeds strictly according to the mechanism of attaching one BDDE molecule to two hydroxyl groups of different HA molecules. In this case, no “suspended” BDDE is formed (Fig. 4) as a reaction product that negatively affects the drug cohesiveness, neither its biodegradation period.

Fig. 4 “Suspended” BDDE. BDDE reacts with one HA molecule, whereas its second functional (epoxy) group is being hydrolyzed (it reacts with water). As can be seen from the figure, in this case, no crosslinking between HA molecules occurs.

As a result of this method of HA crosslinking:

• high cohesiveness is achieved due to the fact that 100% of HA molecules are crosslinked in the preparation
• the duration and uniformity of biodegradation of the drug in the body is expanded
• structure of the resulting preparation allows moisture and nutrients to freely penetrate into the tissues of the body, but prevents the penetration of HA cleavage enzymes into its structure due to their being quite bulky;
• due to the fact that the degree of crosslinking of HA molecules with each other is low, the optimum viscosity is achieved, which allows the drug to be injected into the body using small-diameter needles with no effort.
• the absence of native HA has the following positive outcomes:
• – cohesiveness of the drug;
• – expand the duration and uniformity of biodegradation.

Native HA is disintegrated in the body by hyaluronidase enzyme much faster than its cross-linked analogues. If fragments of native HA are included into the matrix, they will be split first, forming some “foci of cleavage,” resulting in expanded area of possible attack at the HA matrix with hyaluronidase, decreasing the biodegradation period of the drug. Cleavage reactions will also occur in larger quantities specifically in these foci, rather than on the remaining surface of the filler, which will negatively affect the uniformity of biodegradation of the drug in the body.     

Due to the ABSOLUTELY UNIQUE technique for crosslinking HA, Jalor is a product having optimum viscosity for injection with very high cohesiveness, and it is also characterized by long biodegradation period in the body.