The stability of growth hormone in a liquid state is possible only for several days and only when stored in a refrigerator: these kinds of statements are often. Let's say right away that growth hormone is a high-tech, very complex, and fragile product, so this statement was true. Back In 2007. Let's figure out why in 2022 this is no longer relevant:
New information
It turned out that GH is more stable than it was commonly thought, and there is numerous scientific proven evidence data:
For example, in a study conducted by an independent laboratory Daewoong Co Ltd [1], it was found that the damage that the hormone receives when it is in solution for a long time is homogenous and specific:
“…Decomposition products are formed in solutions, including deamidated or sulfoxylated products, and dimeric or polymeric forms may be formed in solution. The predominant chemical degradation reaction of human growth hormone is deamidation, which especially occurs at the asparagine residue at position 149, by direct hydrolysis…” © [1]
It means that instead of molecular degradation according to the domino principle, as it thought before, the most harmful chemical reactions were found. Eliminating or slowing down these reactions will raise the stability of the GH solution to a new level.
And this "trick" was performed by pharmaceutical giants who were able to bring liquid forms of growth hormone to the market and confirm their effectiveness with peer-reviewed studies and patent certifications. [1][2][3]
New technologies
Before obtaining a dry form, growth hormone was subjected to severe dehydration, and even after modifying the lyophilization process specifically for Somatotropin (the drug that is dried, frozen, and then placed in a vacuum chamber, where the solvent is sublimated) the “fragility” of the GR molecule remained very significant. The same discomfort for the end-user was the need for the regular preparation of the solution.
However, empirically, experts concluded that if we change the manufacturing process, then there is no need for lyophilization and sublimation – it will just remain in stable liquid form.
The composition of the liquid into which growth hormone is released during the production process has been changed. Stabilizing agents were added and the resulting solution was so stable, that all experiments showed the superiority of the liquid form over the dry form, both in terms of % damaged GH molecules and in terms of resistance to external influences(including lyophilization and sublimation).
Thus, the most “damaging” steps are excluded from the manufacturing process of the drug, and the resulting liquid form is even more convenient for the end-user.
The solution turned out to be so effective that it passed all the tests and was brought to the market as the finished product.
Therefore, all manufacturers of growth hormone, at the moment, are moving to the new standard for producing a liquid form of the drug.
At this point, it is important to note that although liquid and dry growth hormone are the same substance, there is an important difference in the manufacturing process and the properties of the final product.
It is important to know: No one dissolves liquid growth hormone, it's already synthesized in liquid form and during this production process fragile molecules of HGH are minimally subjected to destructive influences.
Revealing the secrets of patents:
The study described earlier is just one of many. in essence, the task of scientists was to create a stable, convenient form of the drug, effective and safe for humans.
As you understand, this liquid, which contains growth hormone, is a much more advanced solution than the bacteriostatic water for injection from the nearest pharmacy, which is used to dissolve the obsolete dry form.
It is unlikely that the reader will be interested in diving headlong into the intricacies of such a narrow area, however, there is a lot of information in the public domain for those interested: For example, in US patent No. US 6,448,225 relating to Genentech's Nutropin AQ describes an aqueous formulation of human growth hormone-containing human growth hormone, mannitol, a buffer, and a non-ionic surfactant, with citrate buffer being given as preferred. Korean Patent Application No. 10-1999-0001217 provides a stable aqueous formulation in which human growth hormone is dissolved in a buffer solution, which is prepared using a buffer solution of low to moderate acidity, preferably a maleate buffer containing benzalkonium chloride.
I’ll note right away that it’s impossible to patent, r the perpetual motion machine, for example, since the procedure includes substantiating the “effectiveness” of the invention, and not just its “uniqueness” - one more advantage for liquid growth hormone!!!
Stabilizers work!
Let's take a step to the side.
Growth hormone is a very complex molecule (it consists of 191 amino acids, each of them consists of 10 to 30 atoms), and analytical/synthetic methods for studying its behavior in solution are extremely difficult.
The different approach in this area is that they try to empirically answer the question: why does endogenous GR in the human body break down not so quickly as expected and manage to work out at 100%?
Scientists are looking for the factors that allow growth hormone to be more stable in blood than they expected, even at body temperature (and we all know that GH doesn't like high temperatures).
Back in the early 2000s, discoveries were made in the field of the influence of blood pH on the stability of the GR molecule, as well as proteins dissolved in plasma, “poaching” the destructive dipole properties of the liquid.
What are these properties?
And this is an important point.
The fact is that a water molecule is a dipole, that is, it has a positive charge on one side and two negative charges on the other, with these ends, water, like a magnet, can “attach” to molecules and, under the influence of continuous thermal Brownian motion, destroy even crystal lattices, and exhibit the properties of a solvent, and not the weakest, by the way.
Another important term is Solvation (from the Latin solvo “I dissolve”) - the electrostatic interaction between particles (ions, molecules) of a solute and a solvent. Solvation in aqueous solutions is called hydration. The molecular aggregates formed as a result of solvation are called solvates (in the case of water, hydrates).
So, solvation leads to the fact that the type of solvent changes the rate of chemical reactions up to 109 times (!), determines the relative stability of tautomers, conformers, isomers, and affects the reaction mechanism.
In other words, by skillfully selecting "additives" in our main natural solvent, we can control the stability of the compounds contained in it. This is very important and painstaking work since solutions that have shown themselves well in vitro can be inapplicable for human use!
So these approaches to HGH instability in solution were described back in the early 2000s, and judging by the fact that even large pharmaceutical giants have patented [4], certified, and put liquid forms on the market, it already indicates the presence of serious know-how in this area, some patents have already expired, and the secret technologies of big pharmaceutical corporations can be explored, understood and improved.
A small summary is demonstrated by scientific research:
Growth hormone is used clinically in the treatment of people with burns in the United States and China - it significantly accelerates the healing and recovery of patients.
The patients were divided into two groups: one of them received the dry form of HGH, while the other group received the liquid form
In the liquid growth hormone group, the average recovery rate was 38 days (minimum 19, maximum 48) while in the dry group the average rate was 30 however, the minimum was 15 days and the maximum was 60!!! As the result, scientists emphasize that within the limits of mathematical [object Object], as well as the huge difference in cases described before the clinical use of GH, when recovery was much slower, there was no clinical difference between the liquid and dry form.[4]
Scientists have not identified a difference in effectiveness between the dry and liquid forms, however, the convenience of application, and stability of liquid form is a strong advantage.
The liquid form works. Proven.
Let's sum up
- Liquid growth hormone is not a powder dissolved in a "special way", in advance, no. It is a preparation obtained using a different technology, in which there is no need to dry for transportation and storage so less damage to molecule could be made.
- The effectiveness of liquid growth hormone is similar to dry forms; however, ease of application and stability gives the liquid form a competitive advantage and gradually replaces the dry form from the market as obsolete.
[1] WO2004082707A3 - Stabilisation of growth hormones in solution - Google Patents
[2] https://patents.google.com/patent/EP0955062A1/pt
[4] US8409586B2 - Stable liquid formulation of human growth hormone - Google Patents
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