TW202214269A - A special heparinoid composition, with repair, prophylactic and anti-inflammatory effects, applied to the lungs. - Google Patents

Abstract

The present invention provides a special heparinoid composition, with repair, prophylactic and anti-inflammatory effects, applied to the lungs, which includes at least two glycosaminoglycans, which contain 5~95wt% of macromolecular heparin sodium, 3~20wt% of low-molecule-weight heparin sodium and 5~95wt% of dermatan sulfate are formulated into a solution with a mixture to water ratio of 0.1~0.6% by weight, and a delivery device is connected to the patient’s nose or mouth to deliver to the lungs. The composition of this type of heparinoid has an appropriate dose of disaccharide O-sulfate and total sulfates, which can make the blood have an anticoagulant effect. During the prophylactic period, more heparin can be the main body to promote blood circulation, increase oxygen and nutrient delivery capability; during the repair period, if potential bleeding is considered, heparin can be reduced appropriately, but at the same time, the proportion of dermatan sulfate and chondroitin sulfate with anti-inflammatory effects is added to balance the anticoagulation that has a lower risk to cause bleeding while having a special anti-inflammatory effect.

Description

A special heparin-like composition with repairing, health care and anti-inflammatory effects applied to the lungs

The present invention provides a special heparinoid composition that is applied to the lungs and has the functions of repairing, health care and anti-inflammatory, especially the heparinoid composed of a special formula as the main body of anticoagulation, and supplemented by a special delivery device to deliver it to the lungs It can balance anticoagulation that does not cause the risk of bleeding, and has special anti-inflammatory effects.

According to the press, coronavirus (CoV) belongs to a large category of viruses, which can infect humans and vertebrates and cause respiratory diseases, while human infection with coronavirus is mainly respiratory symptoms, and mild symptoms are similar to the common cold, including nasal congestion, runny nose, cough Symptoms of general upper respiratory tract infection such as fever, but severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and severe special infectious pneumonia (commonly known as novel coronavirus (COVID-19) Pneumonia, referred to as new coronary pneumonia (SARS-CoV-2) and other infections, are more severe than ordinary human coronaviruses, and symptoms of acute lower respiratory tract infections such as severe pneumonia and respiratory failure may occur.

In patients with novel coronavirus infection progressing from mild to severe, there will be virus infiltration in bilateral lungs on chest X-ray or ground glass lesions (GGO) on computed tomography (CT). The basic pathological cause of acute respiratory distress syndrome (ARDS) is acute respiratory distress syndrome (ARDS), and the phenomenon of respiratory failure causes oxygenation disorders, septic shock, metabolic acidosis or coagulation dysfunction, etc., and even death, and from pathological From the above, it is mainly due to the deterioration of the alveolar epithelial barrier, the increase of pulmonary microvascular endothelial permeability, excessive immune cell infiltration, and excessive secretion of inflammatory substances, which can cause diffuse acute lung injury, that is, a severe inflammatory reaction diffused with fibrin. (Fibrin) deposits in microvessels and alveoli. In short, the gas in the alveoli and its capillaries cannot be exchanged, and a large number of immune thrombosis (Immuno-thrombosis) will be formed, leading to lung failure. The lungs have no respiratory function and become a dead space, and the current treatment method of acute respiratory distress syndrome , Up to now, supportive treatment is still given, including mechanical ventilation with respirator, oxygen therapy, use of neuromuscular blocking agents or antibiotics/antiviral drugs, infusion therapy, etc.

Furthermore, the clinical and pathological features of the above-mentioned acute respiratory distress syndrome are mainly activation of coagulation and excessive inflammation, among which the increased permeability of the pulmonary microvascular endothelium will cause the new coronary pneumonia virus to pass through. The ACE-2 (angiotensin-converting enzyme 2) receptor on the cell surface enters the cell and causes human infection. For example, the ACE-2 activity of the human body will be significantly reduced due to the infection of the new coronavirus, resulting in ACE-1, Ang II (Angiotensin II) increased significantly, followed by pulmonary edema, severe lung injury and acute lung failure. In addition to virus invasion, severe systemic inflammation, septic shock and other problems often occur.

In most severe and severe patients with new coronary pneumonia, there will be systemic coagulation abnormalities, such as blood clotting in the lungs, heart, liver and kidneys. The reason for coagulation is that the new coronary pneumonia virus can bind to the endothelium. ACE-2 on cells and damage the blood circulation of blood vessels, and then reactive thrombocytosis occurs, resulting in the continuous increase of coagulation factors in the blood. It is activated and generates thrombin (Thrombin) to convert fibrinogen (Fibrinogen) into fibrin (Fibrine), which is deposited in alveoli and interstitial cells, and even caused by the massive formation of diffuse microthrombi (Microthrombi). Systemic inflammatory response, septic shock, multiple organ failure, etc.

In the human immune system, innate immunity is the first line of defense against the invasion of foreign pathogens. When the virus invades the human lungs or other organs, it will summon immune cells to the infection site to initiate an inflammatory response and rapidly When the natural immunity is overloaded, it will stimulate the acquired immune system (Adaptive immunity) to activate specific T cells and B cells (including macrophages, monocytes, dendritic cells) , neutrophils and epithelial cells, etc.) to clean up pathogenic bacteria, but the overreaction of the immune system will lead to the destruction of the vascular endothelium, which will continuously activate the coagulation factor cascade in the blood and cause excessive inflammation, which in turn causes immune thrombosis.

The aforementioned immune thrombus has two main functions, protecting the integrity of endothelial cells. If there is damage, microthrombi will be generated to initiate blood coagulation, and inflammation will progress (in the inflammatory stage, the destruction is more; but in the late stage of inflammation, repair is the main, The role of blood coagulation and coagulation is actually to protect the integrity of endothelial cells), for example, extensive endothelial damage will expose collagen under the endothelium and release tissue factors (TF), namely F III, which is related to coagulation and inflammation. It has a receptor for coagulation factor FV at the N-terminus of F III molecule, which can combine with coagulation factor FV II in plasma to form an active form of TF-FV II a, and then strengthen coagulation factors FX, FXa and FVa to form thrombin. Prothrombinase converts prothrombin into thrombin, which contains a large amount of fibrin and microthrombi, plays an important role in the process of coagulation, is important for cell repair, and provides many immune cells Attach, summon and activate.

In addition, a report published in the Journal of the American College of Cardiology (JACC) showed that the use of anticoagulant drugs (including oral antithrombotics, subcutaneous heparin, and intravenous heparin, blood thinners that slow clotting) can increase hospitalization for new Survival of patients with coronavirus pneumonia, whether in the intensive care unit (ICU) or not, showed improvement after treatment with anticoagulant drugs The drug had higher levels of inflammatory markers than patients who did not receive anticoagulant drugs, suggesting that patients with more severe disease may benefit from anticoagulant drugs earlier. The anticoagulant drugs currently in clinical use include traditional heparin (Un-fractionated Heparin, UFH) and low molecular weight heparin (Low Molecular Weight Heparin, LMWH). There are risks such as bleeding in clinical use, and clinical application is limited. Therefore, with the deepening of clinical and pharmacological research on heparin, low molecular weight heparin is mainly used. Compared with traditional heparin, in addition to having better antithrombotic effect In addition, traditional heparin can only be administered by continuous intravenous infusion or subcutaneous administration. Therefore, how to use heparinoid composed of a special formula as the main body of anticoagulation, supplemented by special delivery equipment to deliver it to the lungs to improve absorption It has the effect of repairing, health care and anti-inflammatory for lung inflammation, which is the direction that those engaged in this industry are eager to study and improve.

Therefore, in view of the above-mentioned deficiencies, the inventor collected relevant information, through various evaluations and considerations, and continued to experiment and modify with years of R&D experience accumulated in this industry, before designing the formula composition of this special effect, supplemented by Special delivery equipment to improve the absorption rate of the lungs and the convenience of the patient's use, the invention patent of the special heparin-like composition applied to the lungs with repair, health care and anti-inflammatory effects was born.

The main purpose of the present invention is to use heparinoid composed of a formula with special efficacy as the main body of anticoagulation, which is based on at least two glycosaminoglycans containing 5-95wt% of macromolecular heparin sodium and 3-40wt% of small molecule heparin. Heparin sodium and 5~95wt% of dermatan sulfate are formulated into a solution with a weight ratio of the mixture to water of 0.1~0.6%, and are delivered to the lungs from the patient's nose or oral cavity through a special delivery device. This heparin-like composition has appropriate disaccharide O-sulfate and total sulfate doses, which can make the blood have anticoagulant effect, and can also use different proportions of heparin in the prevention and repair period to control the desired effect. , in the prevention period, more heparin can be used as the main body to promote blood circulation, increase the oxygen and nutrient transport capacity; in the repair period, if bleeding is considered, an appropriate amount of heparin can be reduced, but at the same time, sulfuric acid skin with anti-inflammatory effect can be added. The composition ratio of chondroitin and chondroitin sulfate is balanced to achieve anti-coagulation that is not easy to cause bleeding risk, and has special anti-inflammatory effect.

The secondary purpose of the present invention is that the heparinoid composed of a special formula can be formulated into a dosage form suitable for use in the nose or respiratory tract of patients, and the delivery equipment such as an ultrasonic atomizer and a nebulizer can be used to directly transfer the heparin by spray or inhalation. After heparinoid is delivered to the lungs through the oral or nasal route of administration, it can improve the absorption rate of the lungs and the convenience of use.

In order to achieve the above-mentioned purpose and effect, the special formula composition of the heparinoid of the present invention includes at least two kinds of glycosaminoglycans, wherein the glycosaminoglycans include but are not limited to the weight percentage (that is, the content of the composition). ) is 5~95wt% of macromolecular liver Macromolecular Heparin Sodium (Macromolecular Heparin Sodium), 3~20wt% of Small Molecular Heparin Sodium (Low-Molecular-Weight Heparin Sodium, LMWH Sodium) and 5~95wt% of Dermatan Sulfate (DS), and dermatan sulfate also Chondroitin Sulfate (CS) can be mixed with 0~15wt%, because Chondroitin Sulfate B contains Iduronic Acid instead of D-Glucuronic Acid , similar to the composition of dermatan sulfate, in this embodiment, the weight-average molecular weight (Mw) of macromolecular heparin sodium is between 5 and 40 kilodaltons (kilo Daltons, hereinafter referred to as kDa). ), the weight-average molecular weight is preferably about 16kDa; the weight-average molecular weight of small molecule heparin sodium is between 0.4 and 15kDa, and the weight-average molecular weight is preferably about 4.4kDa; and the weight-average molecular weight of dermatan sulfate The weight average molecular weight of chondroitin sulfate is between 5 and 50 kDa, and the preferred implementation weight average molecular weight is about 15 kDa.

It can be understood that, in order to distinguish the macromolecular heparin mentioned in the present invention from the small molecular heparin (including heparin sodium, heparin calcium (Heparin Calcium), etc.), the weight average molecular weight (Mw) of traditional heparin (ie unfractionated heparin) About 15kDa, most of the weight average molecular weight is above 5.4kDa, in this embodiment, heparin with a weight average molecular weight above 6kDa can be defined as macromolecular heparin, and heparin with a weight average molecular weight below 6kDa can be defined It is a small molecule heparin, but it is not a limitation when it is actually distinguished.

In this example, the source of heparin used is sulfated glycosaminoglycans (containing large or small molecules of heparin, such as large or small molecules of heparin, extracted from small intestinal mucosa or organ tissues, etc.) from natural animals (such as cattle, pigs, chickens or sharks, etc.). dermatan sulfate, sodium salt of chondroitin sulfate, etc.), or aminogalactose and glucaldehyde extracted from animal cartilage tissue (such as nasal bones, throat bones and trachea, etc.) Acid composition of chondroitin sulfate and dermatan sulfate, etc., and then mixing a certain proportion of large and small molecular heparin to produce heparin with specific molecular weight, dermatan sulfate and/or a mixture without chondroitin sulfate (i.e. heparinoid), to As the main body of anticoagulation, it is dissolved in pure water or deionized water to make a 0.1~0.6% solution (wt/wt, that is, the weight ratio of the mixture to water), and is connected with a special delivery device, which is targeted from the patient. After the heparinoid is delivered to the lungs through the nose or mouth, it can be used to help the lungs to resist blood coagulation and achieve anti-inflammatory, repair, and health care purposes. After the heparinoid composed of the above-mentioned special formula is produced, indicators can also be formulated according to its characteristics. Data, the expected indicators include component verification analysis, solubility, pH tolerance, temperature and humidity tolerance, light tolerance, reversible recovery of activity, organic solvent stability, etc., supplemented by precision instruments for effective monitoring and acquisition. Scientific data as a reference for future process regulation.

The heparin composition of Example 1 has 85wt% macromolecular heparin sodium, 10wt% small molecular weight heparin sodium and 5wt% dermatan sulfate, and is formulated into a 0.2% solution, which can be used alone or with a pharmacologically acceptable compound. Formulations (such as preservatives, glycerin, peppermint, etc.) are used in combination to form a spray solution or solution, and can be delivered to the lungs from the patient's nasal or oral route of administration using a special delivery device. Different proportions of heparin can also be used in the prevention and repair period to control the desired effect. In the prevention period, the proportion of heparin sodium can be increased, and more heparin can be used as the main body to promote blood circulation, increase oxygen and nutrients. Delivery capacity; if bleeding is considered during the repair period, the heparin sodium can be appropriately reduced, but at the same time, the proportion of dermatan sulfate and chondroitin sulfate with anti-inflammatory effect can be added to balance the anticoagulant that does not cause the risk of bleeding. , and has a special anti-inflammatory effect.

In the following examples, only the proportions used in the above-mentioned heparin-like main components are described. Small molecule heparin sodium and 50wt% dermatan sulfate, and formulated into a 0.2% solution; the heparin composition of Example 3 has 10wt% macromolecular heparin sodium, 5wt% small molecule heparin sodium and 85wt% dermatan sulfate , and formulated into a 0.3% solution; the heparin composition of Example 4 has 80wt% of macromolecular heparin sodium, 10wt% of small molecular heparin sodium and 10wt% of dermatan sulfate, and formulated into a 0.3% solution; Example The composition of heparin such as 5 has 7wt% of macromolecular heparin sodium, 3wt% of small molecular heparin sodium and 90wt% of dermatan sulfate, and is formulated into a 0.2% solution; the heparin composition of Example 6 has 7wt% of macromolecules Heparin sodium, 3wt% of small molecular heparin sodium, 88wt% of dermatan sulfate and 2wt% of chondroitin sulfate, and prepared into a 0.2% solution, the proportion, combination and principle of ingredients used in heparinoid composed of this special formula It can be properly regulated according to the actual required efficacy, including in different periods of lung prevention and repair, and can also be applied to other medical applications, such as wound healing and cosmetic efficacy in medical care and repair. , all simple modifications and equivalent changes of the heparin composition made by using the contents of the description of the present invention should be included in the patent scope of the present invention in the same way.

The special delivery equipment for the above-mentioned heparinoid composition is the use of ultrasonic nebulizer (Ultrasonic nebulizer), sprayer (Sprayer), nebulizer (Vaporizer) and other special spray delivery equipment, but not limited to this, Inhalation delivery devices such as Metered Dose Inhalers (MDIs) and nasal inhalers can also be used. When heparin is formulated into oral spray or nasal spray, the spray delivery device can be used once a day or It can be used indoors with a certain dose of about 35kIU (International Unit) for many times; when heparinoid is formulated into an inhalant for administration, a nasal spray inhalation delivery device can be used with a certain dose of about 250~750IU each time. It can be carried and used when going out, so that patients can use the delivery method of spray or inhalation to directly deliver the specially formulated heparinoid to the lungs through the nose or mouth, so as to improve the absorption by the lungs speed and ease of use.

The heparinoid composed of the above-mentioned special formula of the present invention is made based on at least two kinds of glycosaminoglycans, and has appropriate disaccharide (Disaccharide) O-sulfate (O-Sulfo) and appropriate total sulfate doses, and Linked to special delivery equipment, it is delivered to the lungs through the patient's oral or nasal administration route. Since heparin is absorbed from the lungs from the bronchi to epithelial cells and alveoli, and a few enter the venous blood vessels, it can inhibit the coagulation factor. It is not activated and at the same time avoids the generation of thrombin, which can reduce fibrin deposition in tissues and cell proliferation related to fibrinolytic enzymes. Stem cells are transformed and differentiated into cells with specific functions, which can make the blood have better anticoagulant effect, prevent the inflammatory reaction caused by immune thrombosis and lead to lung damage or lung failure, and can also use more heparin as the main body to promote blood circulation, It can fully increase the transport capacity of oxygen and nutrients to increase the oxygen absorption capacity of the lungs and strengthen the pulmonary circulation function. At the same time, adding dermatan sulfate and chondroitin sulfate with anti-inflammatory effect can balance the risk of bleeding. Anticoagulant, but also has special effects of autoimmunity repair, health care and anti-inflammatory.

The above detailed description is only for describing a preferred feasible embodiment of the present invention, but the embodiment is not intended to limit the scope of the patent application of the present invention, and all other equivalent changes and modifications are completed without departing from the technical spirit disclosed in the present invention. Changes should be included in the patent scope covered by the present invention.

To sum up, the above-mentioned special heparinoid composition applied to the lungs with repairing, health-care and anti-inflammatory effects of the present invention can indeed achieve its efficacy and purpose when used, so the present invention is an invention with excellent practicability, It meets the application requirements for an invention patent, and the application is filed in accordance with the law. It is hoped that the review committee can approve the case as soon as possible to protect the inventor's hard work. If you have any doubts, please do not hesitate to send a letter for instructions, and the inventor will do his best to cooperate.

Claims (12)

A special heparin-like composition applied to the lungs with repairing, health-care and anti-inflammatory effects, the heparin-like composition comprises at least two glycosaminoglycans, wherein the glycosaminoglycans comprise 5-95 wt % large Molecular heparin sodium, 3-40wt% small molecular heparin sodium and 5-95wt% dermatan sulfate are prepared into a solution with a weight ratio of the mixture to water of 0.1-0.6%, and a delivery device is connected to deliver the solution from the patient The nasal or oral route of administration is delivered to the lungs for use. A special heparinoid composition applied to the lungs with repairing, health care and anti-inflammatory effects as described in claim 1, wherein the heparinoid composition comprises 85wt% macromolecular heparin sodium, 10wt% small molecular heparin sodium and 5wt% heparin dermatan sulfate, and formulated into a 0.2% solution. According to claim 1, the special heparinoid composition applied to the lungs with repairing, health care and anti-inflammatory effects, wherein the heparinoid composition has 10wt% macromolecular heparin sodium, 40wt% small molecular heparin sodium and 50wt% heparin dermatan sulfate, and formulated into a 0.2% solution. According to claim 1, the special heparinoid composition applied to the lungs with repairing, health care and anti-inflammatory effects, wherein the heparinoid composition has 10wt% macromolecular heparin sodium, 5wt% small molecular heparin sodium and 85wt% heparin dermatan sulfate, and formulated into a 0.3% solution. According to claim 1, the special heparinoid composition applied to the lungs with repairing, health care and anti-inflammatory effects, wherein the heparinoid composition has 80wt% macromolecular heparin sodium, 10wt% small molecular heparin sodium and 10wt% heparin sodium dermatan sulfate, and formulated into a 0.3% solution. According to claim 1, the special heparinoid composition applied to the lungs with repairing, health care and anti-inflammatory effects, wherein the heparinoid composition has 7wt% macromolecular heparin sodium, 3wt% small molecular heparin sodium and 90wt% heparin sodium dermatan sulfate, and formulated into a 0.2% solution. According to claim 1, the special heparinoid composition applied to the lungs with repairing, health care and anti-inflammatory effects, wherein the weight average molecular weight of the macromolecular heparin sodium is between 5 and 40 kDa, and the weight of the small molecular heparin sodium is between 5 and 40 kDa. The average molecular weight is between 0.4 and 15 kDa, and the weight average molecular weight of dermatan sulfate is between 5 and 80 kDa. According to claim 7, the special heparinoid composition applied to the lungs with repairing, health care and anti-inflammatory effects, wherein the weight average molecular weight of the macromolecular heparin sodium is 16kDa, and the weight average molecular weight of the small molecule heparin sodium is 4.4kDa, And the weight average molecular weight of dermatan sulfate is 30 kDa. A special heparinoid composition applied to the lungs with repairing, health care and anti-inflammatory effects as described in claim 1, wherein the heparinoid composition further comprises 0-15wt% chondroitin sulfate, and the weight average molecular weight of the chondroitin sulfate is between 5 and 50 kDa. According to claim 9, the special heparinoid composition applied to the lungs with repairing, health care and anti-inflammatory effects, wherein the heparinoid composition has 7wt% macromolecular heparin sodium, 3wt% small molecular heparin sodium, 88wt% heparin Dermatan sulfate and 2wt% chondroitin sulfate were formulated into a 0.2% solution. According to claim 9, the special heparinoid composition applied to the lungs with repairing, health-care and anti-inflammatory effects, wherein the weight-average molecular weight of the chondroitin sulfate is 15kDa. The special heparin-like composition that is applied to the lungs with repairing, health-care and anti-inflammatory effects as described in claim 1, wherein the delivery device is an ultrasonic atomizer, a metered dose inhaler or a nasal inhaler.