RU2846745C1 - Method for delivering orally administered preparations to human lungs - Google Patents

Abstract

FIELD: medical science.

SUBSTANCE: invention refers to medicine, namely to therapy, pulmonology, and may be used for the delivery of orally administered preparations to human lungs. Preparation delivered to lungs is dissolved in Dimexide solution. Patient is placed in a horizontal position on his/her back, an oesophagus is blocked by means of a cylinder dilator, and the preparation dissolved in the solution Dimexide is administered orally.

EFFECT: method enables the preparation delivery directly into the patient’s lungs ensured by the preparation transfer through the oesophageal mucosa into the oesophageal lymphatic system and further into the pulmonary lymphatic system.

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Description

The invention relates to the field of medicine, namely to methods of delivering drugs to the lungs, and can be used to treat the lungs [A61M 31/00, A61M 37/00].

A METHOD FOR TREATING LUNG CANCER USING RADIOMODIFIERS is known from the prior art [RU2146161C1, 10.03.2000], which includes endobronchial delivery of a medicinal mixture directly to the tumor followed by radiation therapy, characterized in that, in the event of a violation of regional blood flow and bronchial patency for 0.5 - 1.0 hours before the radiation therapy session, 3.0 ml of a radiomodifying mixture containing 1.0 ml of brikanil, 1.0 ml of aminophylline with the addition of 1.0 ml of dimexide is injected in discrete portions of 2.5 - 3.0 μl using an electronic microdoser.

The disadvantage of the analogue is the use of endobronchial administration of the medicinal mixture, which may result in complications, the presence of contraindications, which include severe cardiac arrhythmias, acute respiratory failure with hypercapnia.

Also known is a METHOD FOR TREATMENT OF LUNG CANCER [SU1522502A1, published 30.04.1991], characterized by the fact that the nature of blood circulation and ventilation in the lung affected by the tumor are first determined, while maintaining the ventilation capacity and there is a pronounced circulatory disorder in the lung affected by the tumor, before the radiation therapy session, inhalation of a medicinal mixture is carried out: 1.0-2.0 ml of a 24% solution of euphyllin, 1.0-2.0 ml of a 0.05% solution of alupent and 1.0-2.0 ml of dimexide.

The disadvantage of the analogue is the low efficiency of drug delivery due to the use of the inhalation method of drug administration, which has such disadvantages as the deposition of a significant portion of the drug on the mucous membrane of the upper respiratory tract, a high content of large particles in the aerosol that adsorb small ones, which further reduces the amount of drug reaching the bronchioles and hinders the absorption of inhaled substances by the mucous membrane.

A METHOD FOR TREATMENT OF RADIATION INJURIES TO THE LUNG [RU2487706, published: 03.11.2011], complicated by abscess formation, is known, which involves the use of anti-inflammatory drugs such as corticosteroids, antibiotics and inhalations with a 10% solution of dimethyl sulfoxide; bronchodilators, mucolytics, antiplatelet agents, antihistamines, antitussives, breathing exercises and oxygen therapy, characterized in that the treatment is carried out in a hospital setting, where, in parallel with anti-inflammatory steroidal and non-steroidal, bronchodilators, mucolytics and antiplatelet agents, detoxifying, analgesic, hemostatic, antitussive agents, artificial hypotension, and sanitation of the abscess cavity are used, with these agents being used until the pain syndrome is relieved, body temperature is normalized, the general condition is stabilized, cough and shortness of breath are reduced, then replacement, metabolic, reparative and immune agents are added, and the treatment is carried out until the Karnovsky functional state index is stabilized at a level of 60-80%, with a decrease in the volume of discharge from the abscess cavity by 50% or its disappearance, the patient is transferred to outpatient treatment with another hospitalization when the index decreases Karnovsky up to 40-50%, QOLi-NS index up to 25 points and deterioration of the radiographic picture, while in addition to corticosteroids, non-steroidal anti-inflammatory drugs are used: xefocam, 10-15% solution of dimexide in inhalations, erespal.

The main technical problem of the prototype, as well as of the above-mentioned analogue, is the low efficiency of drug delivery due to the use of the inhalation method of administration, which has such disadvantages as the deposition of a significant portion of the drugs on the mucous membrane of the upper respiratory tract, a high content of large particles in the aerosol that adsorb small ones, which further reduces the amount of drug reaching the bronchioles and hinders the absorption of inhaled substances by the mucous membrane.

The objective of the invention is to eliminate the shortcomings of analogues and prototypes.

The technical result of the invention consists in increasing the efficiency of drug delivery to the lungs.

The said technical result is achieved due to the fact that the method for delivering orally administered drugs to the lungs of a person, characterized by the fact that the drug delivered to the lungs is dissolved in a solution of dimexide, the patient is placed in a horizontal position on his back, the esophagus is blocked with a balloon dilator and the drug dissolved in the dimexide solution is administered orally, while with the help of dimexide the drug is transferred through the mucous membrane of the esophagus into the lymphatic system of the esophagus, and the outflow of lymph of the lymphatic system of the esophagus transfers the drug into the lymphatic system of the lungs.

In particular, the dilation time is 3-5 minutes.

In particular, the balloon dilator is placed in the area of the middle - bronchial or lower - diaphragmatic narrowing of the esophagus.

Fig. 1 shows a chest X-ray using a contrast agent.

Fig. 2 shows an X-ray of the lungs using a radiopaque substance dissolved in a solution of dimethyl sulfoxide.

Fig. 3 shows a radiograph of the lungs using a radiopaque substance dissolved in a solution of dimethyl sulfoxide with dilation of the esophagus.

Implementation of the invention.

The essence of the invention lies in the introduction of drugs (medicines, vitamins, hormonal, etc.) into the lungs through the lymphatic system of the esophagus.

From the source Shishko V.I., Petrulevich Yu.Ya. GERD: anatomical and physiological features of the esophagus, risk factors and development mechanisms (literature review, part 1) // Journal of Grodno State Medical University. 2015, No. 1. pp. 19-25 [https://www.gastroscan.ru/literature/authors/8192] it is known that the outflow of lymph from the esophagus is carried out either towards the lymph nodes of the perigastric region, or to the lymph nodes of the pharynx. From the cervical and upper third of the thoracic esophagus, the lymphatic vessels go to the deep cervical nodes, pretracheal and paratracheal, tracheobronchial and posterior mediastinal nodes. From the middle third of the thoracic esophagus, the ascending vessels reach the aforementioned nodes of the chest and neck, while the descending vessels reach the abdominal cavity: the gastric, pyloric, and pancreaticoduodenal nodes. Vessels from the rest of the esophagus also drain into these nodes.

Based on this, in the present invention, in order to increase the efficiency of drug delivery to the human lungs, it is proposed to use the delivery of drugs from the esophagus through the lymph, while it is necessary to solve two problems

1) the mucous membrane of the esophagus is multilayered and consists of squamous epithelium and makes it difficult or does not allow substances to be absorbed through it;

2) The short residence time of the drug in the esophagus with traditional oral administration, and upon passage through the gastrointestinal mucosa, the drug enters the general bloodstream via the liver. In the liver, the drug is rapidly transformed or possibly inactivated (first-pass effect, excretion before entering the general bloodstream, bioavailability).

To solve the first problem, a highly permeable solution of dimexide is used to deliver water-soluble drugs to the lungs.

To solve the second problem, to ensure the absorption of the drug solution and dimexide through the esophageal mucosa and prevent it from entering the gastrointestinal tract, the patient is placed horizontally and the esophagus is blocked using a balloon dilator.

Dimexide is a clear, colorless liquid with a slight, distinctive odor and slight tints of light yellow. The main active ingredient is dimethyl sulfoxide (DMSO). DMSO is known for its ability to enhance transdermal transport. DMSO can penetrate the skin barrier in an average of 7 seconds, carrying dissolved active ingredients from cosmetics or medications. By dramatically increasing the rate of penetration through the skin, DMSO enhances the effectiveness of creams, ointments, and solutions. DMSO also has strong solubility.

A balloon dilator is an endoscopic instrument consisting of a long catheter with a coiled balloon at its distal end. A special instrument is used to inject fluid into the balloon, creating a specific pressure. This causes the balloon to expand and expand to a specific diameter.

The drug is delivered to the lungs as follows.

The water-soluble drug required for delivery to the lungs is dissolved in a DMSO solution. The patient is placed in a horizontal position. Esophageal dilation is performed according to protocol. A balloon dilator is inserted into the esophagus under fluoroscopic guidance and positioned at the site of the middle (bronchial) or, preferably, lower (diaphragmatic) esophageal stenosis. Once positioned, fluid is pumped into the balloon, inflating it, which in turn occludes the esophagus.

A solution of dimethyl sulfoxide and the drug is administered orally. Due to esophageal dilation, the drug solution is retained in the esophagus, preventing it from entering the gastrointestinal tract. Due to the properties of dimethyl sulfoxide, it penetrates the esophageal mucosa into the esophageal lymphatic system. Once there, the drug is carried by lymphatic drainage into the pulmonary lymphatic system.

Thanks to Dimexide, the drug easily penetrates the esophageal mucosa and enters the esophageal lymphatic system, and the connection of the esophageal lymphatic system with the lymphatic system of the lungs allows the drug to be transported to the lungs, where the drug exhibits its properties.

The balloon is inflated for several minutes, typically 3-5 minutes, to maximize penetration of the DMSO solution and the medication through the esophageal mucosa. Afterward, the balloon is deflated and removed. Increasing the esophageal dilation time beyond this time is not beneficial, as this will allow the maximum amount of DMSO solution and medication to pass through the esophageal mucosa. Furthermore, increasing the time may increase the risk of complications typical of balloon dilation of the esophagus, including pain, bleeding, esophageal perforation, and reactions to anesthesia or sedation. Reducing the esophageal dilation time below this time reduces the amount of DMSO solution and medication permeating the esophageal mucosa.

To achieve the stated technical result—namely, effective drug delivery to the lungs—the inventor conducted a series of experiments. The radiopaque agent Omnipaque was chosen as the drug to be delivered to the lungs. It is easily detectable in the lungs using X-rays and serves as an indicator in the experiments, allowing for an objective assessment of the feasibility of the method being tested for drug delivery to the lungs. The experiments below are not presented in chronological order, but rather to illustrate the increasing degree of contrast, from less to more.

Experiment #1:

oral administration of Omnipaque 100;

exposure - 30 min;

X-ray control.

Research protocol dated 04.06.2024 (see Fig. 1)

Patient: Nikolai B.

Date of birth: January 1, 1947

Gender: Male

Purpose of the study: Dynamic observation

Chest X-ray

Anatomical region: OGP

Equipment: Stationary RDK (tripod table) "Precision"

Contrast: Omnipaque 100

Input method: peros

Who introduced: Independently

Allergic reactions: No.

ED = 0.02 mSv.

Experiment #2:

oral administration of Omnipaque 100 / Dimexide 25% 100 in a ratio of 1:1, a total of 200 ml;

exposure - 30 min;

X-ray control.

Research protocol dated March 28, 2024 (see Fig. 2)

Patient: Nikolai B.

Date of birth: January 1, 1947

Gender: male

Purpose of the study: Dynamic observation

Chest X-ray

Anatomical region: OGP

Equipment: Stationary RDK (tripod table) "Precision"

Contrast: Omnipaque 100 / Dimexide 25%

Input method: peros

Who introduced: Independently

Allergic reactions: No

Exposure: 30 min

ED = 0.02 mSv.

Experiment #3:

esophageal dilation;

oral administration of Omnipaque 100 / Dimexide 25% 100 in a ratio of 1:1, a total of 200 ml;

exposure - 5 min;

dilatant extraction;

exposure – 25 min;

X-ray control.

Research protocol dated 05/14/2024 (see Fig. 3)

Patient: Nikolai B.

Date of birth: January 1, 1947

Gender: Male

Purpose of the study: Dynamic observation

Chest X-ray

Anatomical region: OGP

Equipment Stationary RDK (table-tripod) "Precision"

Contrast: Omnipaque 100.0/Dimexide 25% 100 Omnipaque 100/Dimexide 25% 100 in a 1:1 ratio, a total of 200 ml

Route of administration: per os with dilation of the esophagus

Allergic reaction: No.

ED = 0.02 mSv.

In the radiograph shown in Fig. 3, the lungs are more clearly visible than in the radiographs shown in Figs. 1-2, while in the radiograph shown in Fig. 2, the lungs are more clearly visible than in the radiograph shown in Fig. 1. This demonstrates the effectiveness of the delivery of the radiocontrast agent dissolved in the dimexide solution during oral administration with esophageal dilation, compared to oral administration of the drug without dimexide and without esophageal dilation. The obtained results of applying the claimed method for drug delivery to the lungs and the analysis of radiographs demonstrate its effectiveness due to the high permeability of dimexide, which, during esophageal dilation, allows the drug to be "conducted" through the esophageal mucosa into the esophageal lymphatic system, and from there, due to lymph outflow, into the lymphatic system of the lungs, where the drug exhibits its therapeutic, prophylactic, and other characteristic properties.

Claims (3)

1. A method for delivering orally administered drugs to the lungs of a person, characterized in that the drug to be delivered to the lungs is dissolved in a solution of dimexide, the patient is placed in a horizontal position on his back, the esophagus is blocked using a balloon dilator and the drug dissolved in the dimexide solution is administered orally, while with the help of dimexide the drug is transferred through the mucous membrane of the esophagus into the lymphatic system of the esophagus, and the outflow of lymph of the lymphatic system of the esophagus transfers the drug into the lymphatic system of the lungs. 2. The method according to paragraph 1, characterized in that the dilation time is 3-5 minutes. 3. The method according to paragraph 1, characterized in that the balloon dilator is placed in the area of the middle - bronchial or lower - diaphragmatic narrowing of the esophagus.