Patent Application
20180161276
This application claims priority to Taiwan Application Serial Number 105141456, filed Dec. 14, 2016, which is herein incorporated by reference.
The present disclosure relates to a temperature-responsive composition. More particularly, the present disclosure relates to a temperature-responsive composition, method for fabricating and use the same capable of prolonging the half-life of the nitric oxide.
Nitric oxide (NO) has a higher diffusion rate, penetrates through a cell membrane easily and is unstable so as to be an intercellular or intracellular signal molecule. That is, nitric oxide can be an effective signal for adjusting respiratory system, digestive system and endocrine and metabolic system of an advanced organism. Recently, nitric oxide is further provided for treating cardiovascular system, immune system, cancer or skeletal system and even can accelerate a healing of a wound so as to be attended extensively.
Functions of nitric oxide for bone metabolism have been studied recently when nitric oxide is utilized as a therapeutic gas. With the extension of human life, osteoporosis becomes second most-common disease according to the analysis of the world health organization, and a serious bone fracture even results in death. It is known that cytokines, such as interleukin-1 (IL-1), tumor necrosis factor (TNF) and interferon-γ (IFN-γ), will affect the activity of nitric oxide synthase (NOS) of a bone tissue. When the concentration of the accumulated nitric oxide achieves a proper level, the formation of osteoclasts and the function of mature osteoclasts will be inhibited. Otherwise, the function of osteoblasts will be affected and even the bone resorption of the osteoclasts will be prompted when the concentration of the accumulated nitric oxide is insufficient.
In addition, a half-life of nitric oxide is quite short due to a self-oxidation of nitric oxide or a reaction between nitric oxide and erythrocyte in plasma or ceruloplasmin. Thus, nitric oxide is limited for medical applications.
The present disclosure provides a temperature-responsive composition. The temperature-responsive composition includes a nitric oxide donor and a carrier. The nitric oxide donor is a pH-dependent material, and the carrier includes a protective agent and an organic proton acid for carrying the nitric oxide donor with an effective amount. Furthermore, a transition temperature of the temperature-responsive composition is larger than or equal to 28° C. and less than or equal to 37° C.
The present disclosure further provides a method for fabricating the temperature-responsive composition as mentioned above. The method includes providing an oil phase solution, providing a water phase solution, performing an emulsification and collecting the temperature-responsive composition. In the step of providing the oil phase solution, the oil phase solution includes the nitric oxide donor, the protective agent and the proton acid. Then, the step of performing the emulsification is achieved by mixing the oil phase solution and the water phase solution for forming the temperature-responsive composition. Finally, the temperature-responsive composition will be collected.
The present disclosure further provides a method for treating indications for nitric oxide therapy, and the method includes administering an effective amount of the above-mentioned temperature-responsive composition to a subject suffered from the indications for nitric oxide therapy.
The present disclosure can be more fully understood by reading the following detailed description of the embodiment, with reference made to the accompanying drawings as follows:
Please refer to
The carrier 120 includes a protective agent and an organic proton acid. In particular, the organic proton acid can be provided for adjusting the acidity of the environment of the nitric oxide donor 110 and has functions, such as amphiphilic and phase-changeable, so as to stabilize nitric oxide-containing bubbles. More particularly, the organic proton acid can be capric acid or lauric acid.
The protective agent can prevent the nitric oxide donor 110 from decomposing quickly, which is caused by the organic proton acid. The selection and the content of the protective agent of the carrier 120 can be further adjusted corresponding to the organic proton acid. In particular, a transition temperature of the temperature-responsive composition 100 can be larger than or equal to 28° C. and less than or equal to 37° C. Thus, the temperature-responsive composition 100 is a solid at room temperature, such as 25° C. Then, the temperature-responsive composition 100 will change its phase due to a body temperature of the human body in the following application. More particularly, the transition temperature of the temperature-responsive composition 100 is between a first melting point of the protective agent and a second melting point of the organic proton acid by adjusting a mixing ratio of the protective agent and the organic proton acid of the carrier 120. When the organic proton acid of the carrier 120 is capric acid with a melting point of 31.6 OC and the protective agent of the carrier 120 is octadecane with a melting point between 28° C. and 30° C., for example, the protective agent and the organic proton acid can be mixed at a weight ratio of the protective agent to the organic proton acid of 1:0.25 to 1:4. Accordingly, the transition temperature of the temperature-responsive composition 100 can be set up to be larger than or equal to 28° C. and less than or equal to 37° C. It is noted that the protective agent can be but not limited to nonadecane, icosane, 1-Tetradecanol or hexadecan-1-ol when the organic proton acid is capric acid. Moreover, the organic proton acid can be lauric acid with a melting point between 44° C. and 46° C., and the protective agent can be selected from an alkane or alkanol with a lower melting point, such as C11-C16 alkane or C11-C12 alkanol, to allow the transition temperature of the temperature-responsive composition 100 to be less than or equal to 37° C.
Accordingly, except the temperature-responsive composition 100 of the present disclosure can be stored easily at a low temperature, such as 4° C., it also can be changed from a solid state to a melted state due to the body temperature of the human body in the following medical application. Thus, the nitric oxide donor 110 will further react with the organic proton acid of the melted carrier 120 to produce nitric oxide-containing bubbles in plasma.
Please refer to
In details, Step S200 and Step S202 provide an oil phase solution and a water phase solution, respectively. In order to avoid the nitric oxide donor from reacting with the organic proton acid quickly, the nitric oxide donor is mixed with the protective agent at first for obtaining a first solution. The first solution is then mixed with a second solution containing the organic proton acid for obtaining the oil phase solution.
In Step S204, the oil phase solution obtained from Step S200 is mixed with the water phase solution obtained from Step S202 to perform an emulsification for forming the temperature-responsive composition.
In Step S206, the temperature-responsive composition can be collected by steps of filtering, washing and drying.
Accordingly, the temperature-responsive composition, which is fabricated from the above-mentioned steps, can be utilized as one of drug ingredients for treating indications for nitric oxide therapy, for example, osteoporosis. Furthermore, the drug can include a pharmaceutically acceptable salt.
The temperature-responsive composition has been described as mentioned above. In the following, a first embodiments and a second embodiment will be further provided to illustrate the above-mentioned temperature-responsive composition, the method for fabricating thereof and the accompanied effect in details. However, the present disclosure is not limited thereto.
Please refer to
The microfluidic system 300 includes a first infusion pump 310, a second infusion pump 320, a third infusion pump 330, a transmission unit 340, a collecting unit 350 and three tubes 310a, 320a, 330a for connecting the first infusion pump 310, the second infusion pump 320 and the third infusion pump 330, respectively, to the transmission unit 340.
In the 1st embodiment, the transmission unit 340 is set up by polishing a 26G needle with a gauge diameter of 0.45 mm and then embedding the 26G needle into an 18G stainless steel needle (1.2 mm). Then, the first solution and the second solution are prepared separately. In particular, 5 mg of a nitric oxide donor is evenly dispersed in a protective agent to form a first solution. More particularly, the protective agent of the 1st embodiment is 99% octadecane, the nitric oxide donor is diethylenetriaine-NONOate, and the second solution contains 98% capric acid.
The first solution and the second solution are loaded into the tube 310a and the tube 320a, respectively, by the first infusion pump 310 and the second infusion pump 320. Then, the first solution and the second solution are mixed uniformly at an intersection A of the tube 310a and the tube 320a for forming an oil phase solution. Preferably, a weight ratio of the protective agent (that is, octadecane) to the organic proton acid (that is, capric acid) in the oil phase solution is 1:3 so that the transition temperature of the temperature-responsive composition of the 1st embodiment is 29.5±0.7° C.
In the 1st embodiment, a polyvinyl alcohol (PVA) solution is provided as a water phase solution. The polyvinyl alcohol solution is loaded into the tube 330a by the third infusion pump 330 and mixed with the oil phase solution at an intersection B of the tube 330a and the transmission unit 340 to perform an emulsification for forming the temperature-responsive composition, and the temperature-responsive composition will flow into the collecting unit 350 along with the polyvinyl alcohol solution. In addition, the tube 310a, the tube 320a, the tube 330a and the transmission unit 340 can be placed in a warm bath to allow the above-mentioned steps to be performed at a predetermined temperature. Preferably, the predetermined temperature ranges from 55° C. to 60° C.
A filter paper is finally provided to remove the polyvinyl alcohol solution and filter out the temperature-responsive composition. The temperature-responsive composition is then washed by a phosphate buffered saline (PBS) solution and air-dried at 4° C. for the following analysis and application.
It is noted that diethylenetriaine-NONOate is water-soluable and decomposed easily by capric acid. Thus, diethylenetriaine-NONOate is dispersed in octadecane at first in the 1st embodiment and loaded into an individual channel for reducing the probability of the above-mentioned decomposition. Moreover, it is favorable to perform the emulsification of Step S204 in the microfluidic system 300 for forming the temperature-responsive composition with a uniform particle size. However, the emulsification of Step S204 also can be performed by stirring or homogenizing.
Please refer to
In
In particular, the temperature-responsive composition is a sphere microparticle as shown in
A temperature-responsive composition of the 2nd embodiment and a method for fabricating thereof are similar to the 1st embodiment. However, a weight ratio of octadecane to capric acid in a carrier is different from the 1st embodiment so that a transition temperature of the temperature-responsive composition herein is different from that of the 1st embodiment. The weight ratio of octadecane to capric acid in the carrier, the corresponding transition temperature of the temperature-responsive composition and NO level per milligram of the temperature-responsive composition are listed in Table 1.
As shown in Table 1, the amount of nitric oxide released by the temperature-responsive composition is higher than that of the 1st embodiment when the weight ratio of octadecane to capric acid in the carrier is 3.5:1. That is, the temperature-responsive composition of the 2nd embodiment also has a good coverage for diethylenetriaine-NONOate. Moreover, the promotion of the transition temperature of the temperature-responsive composition in the 2nd embodiment is favorable for further application.
Please refer to
As mentioned above, diethylenetriaine-NONOate is a pH-dependent material. Accordingly, diethylenetriaine-NONOate is decomposed quickly for producing nitric oxide when the acidity of the operating environment changes from 7.4 to 6.0. Thus, a plurality of nitric oxide-containing bubbles 400 will be produced in the phosphate buffered saline solution as shown in
Accordingly, there are nitric oxide-containing bubbles 500 produced in the silicone oil as shown in
Please refer to
Please refer to
As mentioned above, the half-life of nitric oxide is quite short due to the reaction between nitric oxide and erythrocyte in plasma or ceruloplasmin. Please refer to
Compared to the half-life of nitric oxide, which is produced by using diethylenetriaine-NONOate in the absence of hemoglobin (Hb), the half-life of nitric oxide, which is produced by using diethylenetriaine-NONOate in the presence of hemoglobin, has a degradation of 85% as shown in
To sum up, osteoporosis can be prevented from several aspects by using the temperature-responsive composition of the present disclosure. First, nitric oxide produced by reacting the nitric oxide donor with the organic proton acid after phase changing is capable of adjusting the bone cell growth and differentiation and inhibiting the function of the osteoclasts. Second, the organic proton acid can provide protons for stabilizing the produced nitric oxide and inhibiting the differentiation of the osteoclasts. Finally, a loading frequency of nitric oxide can be reduced substantially by extending the half-life of the produced nitric oxide so as to increase the convenience for preventing and treating osteoporosis.
Although the present disclosure has been described in considerable detail with reference to certain embodiments thereof, other embodiments are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description of the embodiments contained herein.
It will be apparent to those skilled in the art that various modifications and variations can be made to the structure of the present disclosure without departing from the scope or spirit of the disclosure. In view of the foregoing, it is intended that the present disclosure cover modifications and variations of this disclosure provided they fall within the scope of the following claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 105141456 | Dec 2016 | TW | national |
