JP6937065B1 - Therapeutic agent for interstitial pneumonia - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an effective, safe and inexpensive treatment for interstitial pneumonia. A pharmaceutical composition for treating interstitial pneumonia, which comprises vitamin C and / or a derivative thereof, and an adjunct to the treatment of interstitial pneumonia, which comprises vitamin C and / or a derivative thereof. [Selection diagram] None

Description

The present invention relates to therapeutic agents and therapeutic aids for interstitial pneumonia containing vitamin C and / or its derivatives.

Interstitial pneumonia is a disease that causes inflammation of the interstitium of the lungs. As inflammation progresses, the alveolar wall thickens and lung function declines. Interstitial pneumonia includes idiopathic interstitial pneumonia of unknown cause and secondary interstitial pneumonia of unknown cause, and many patients have idiopathic interstitial pneumonia. For the treatment of interstitial pneumonia, steroids, immunosuppressants, antifibrotic agents, respiratory rehabilitation, oxygen therapy, lung transplantation and the like are used (see Non-Patent Document 1 and the like). However, interstitial pneumonia remains a difficult disease to treat. Moreover, there are concerns about side effects of drug therapy. There is also a problem that the cost of treatment increases when an antifibrotic drug is used.

Japanese Respiratory Society Diffuse Pulmonary Disease Diagnosis and Treatment Guideline Development Committee ed .: Guideline for Diagnosis and Treatment of Idiopathic Interstitial Pneumonia, Revised 3rd Edition, Nankodo, Tokyo, 2016.

Effective, safe and inexpensive treatment of interstitial pneumonia is desired.

The present inventors conducted diligent studies to solve the above problems, and found that when vitamin C was administered to a patient with interstitial pneumonia, the symptoms were improved or the progression was suppressed, and the present invention was completed. I arrived.

Therefore, the present invention provides:
(1) A pharmaceutical composition for treating interstitial pneumonia, which comprises vitamin C and / or a derivative thereof.
(2) The pharmaceutical composition according to (1), which contains a single dose of 25 g or more of vitamin C and / or a derivative thereof, and is administered at least once every two weeks.
(3) The pharmaceutical composition according to (1) or (2), which is used in combination with alkalizing therapy.
(4) An adjunct to the treatment of interstitial pneumonia, which comprises vitamin C and / or a derivative thereof.
(5) The agent according to (4), which contains vitamin C and / or a derivative thereof in a single dose of 25 g or more and is administered at least once every two weeks.
(6) The agent according to (4) or (5), which is used in combination with alkalizing therapy.

According to the present invention, interstitial pneumonia can be effectively treated. According to the present invention, it is possible to effectively assist in the treatment of interstitial pneumonia. Vitamin C used in the pharmaceutical composition and therapeutic aid of the present invention is a highly safe substance used as a food raw material or a food additive. Moreover, vitamin C is inexpensive. Therefore, the pharmaceutical composition and therapeutic aid of the present invention not only exert an excellent effect in the treatment of interstitial pneumonia, but are also safe and inexpensive. Furthermore, the pharmaceutical compositions and therapeutic aids of the present invention have the effect of reducing the side effects of conventional treatments for interstitial pneumonia.

It is a graph which shows the transition of the blood KL-6 of the patient of Example 1. From around January 2019, the administration of vitamin C was increased from 25 g once a month to 25 g once a week. It is a graph which shows the transition of the blood KL-6 and SP-D of the patient of Example 2. It is a graph which shows the transition of the blood KL-6 and SP-D of the patient of Example 3. The time course of the chest CT image of the patient of Example 3 is shown. It is a graph which shows the transition of blood KL-6 and SP-D after the resumption of vitamin C therapy in the patient of Example 4. It is a chest X-ray photograph before resumption of vitamin C therapy (left panel) and after resumption (right panel) in the patient of Example 4. It is a chest CT image before resumption of vitamin C therapy (upper panel) and after resumption (lower panel) in the patient of Example 4.

The present invention provides, in one embodiment, a pharmaceutical composition comprising vitamin C and / or a derivative thereof for treating interstitial pneumonia.

Vitamin C may be in free form or in salt form such as sodium salt. Examples of vitamin C derivatives include sodium ascorbic acid phosphate, magnesium ascorbic acid phosphate, 2-glucoside ascorbic acid, 3-O-ethylascorbic acid, ascorbic tetrahexyldecanoate, ascorbyl palmitate, and the like. Not limited.

Interstitial pneumonia includes idiopathic interstitial pneumonia of unknown cause and secondary interstitial pneumonia of known cause. Idiopathic interstitial pneumonia is divided into major idiopathic interstitial pneumonia, rare idiopathic interstitial pneumonia, and unclassifiable idiopathic interstitial pneumonia. The major idiopathic interstitial pneumonia is idiopathic pulmonary fibrosis, idiopathic nonspecific interstitial pneumonia, respiratory bronchitis interstitial lung disease, exfoliative interstitial pneumonia, idiopathic organizing pneumonia, and It is divided into acute interstitial pneumonia. Rare idiopathic interstitial pneumonia is divided into idiopathic lymphocytic interstitial pneumonia and idiopathic upper lobe pulmonary fibrosis. Causes of secondary interstitial pneumonia include, but are not limited to, collagen disease, inorganic dust, organic dust, drugs, radiation therapy, and the like. In the present specification, the term interstitial pneumonia may be any of the above types of interstitial pneumonia. The pharmaceutical composition of the present invention has a therapeutic effect on any of the above types of interstitial pneumonia.

As used herein, treatment of interstitial pneumonia includes elimination, amelioration, and suppression of progression of interstitial pneumonia. In addition, treatment of interstitial pneumonia includes prevention of interstitial pneumonia. Prevention of interstitial pneumonia includes preventing the development of interstitial pneumonia and suppressing or delaying the development of interstitial pneumonia.

The pharmaceutical composition of the present invention can be produced by using known means and methods.

The route of administration of the pharmaceutical composition of the present invention is not particularly limited, but is preferably intravenous administration or intraperitoneal administration, and more preferably intravenous administration. Intravenous and intraperitoneal formulations are known. Examples of the dosage form for intravenous administration include injections and infusions. Usually, these formulations contain a carrier. Carriers suitable for these formulations are known and can be appropriately selected and used. Examples of the carrier include, but are not limited to, water for injection, physiological saline, glucose solution, a mixture thereof, Ringer's solution and the like. Typically, the pharmaceutical compositions of the invention are administered intravenously by infusion.

The dose of vitamin C or a derivative thereof according to the pharmaceutical composition of the present invention is about 2 g to about 200 g, preferably about 20 g to about 100 g, and more preferably about 25 g to about 25 g to about 200 g, preferably about 20 g to about 100 g, when infused to an adult weighing 70 kg. It is 50 g. The pharmaceutical composition of the present invention may be administered by infusion, for example, once or twice every 1 to 2 weeks. The pharmaceutical composition of the present invention is usually administered once a day. The dose, frequency, and duration of administration of vitamin C or a derivative thereof according to the pharmaceutical composition of the present invention are the severity and progression of interstitial pneumonia (eg, radiograph, CT image, or KL-6, SP). -D may be determined based on marker values, etc.), treatment of other interstitial pneumonia to be combined, patient's weight and age, patient's health condition, pre-existing disease and its treatment, etc. can do. A typical example of administration of a preferable vitamin C or a derivative thereof is a single dose of 25 g or more (for example, 25 g to 50 g, about 25 g to about 100 g, about 25 g to about 200 g, etc.) and at least once every two weeks (for example, once every two weeks or more). For example, once every two weeks, twice every two weeks, three times two weeks, four times two weeks, once a week, twice a week, etc.).

The pharmaceutical composition of the present invention may be used in combination with other treatments for interstitial pneumonia. Treatment of interstitial pneumonia includes drug therapy with steroids, immunosuppressants, or antifibrotic agents (eg, pirfenidone, nintedanib); oxygen therapy; respiratory rehabilitation; lung transplantation, etc. Not limited to treatment. In the case of secondary interstitial pneumonia, treatment for eliminating the cause is also performed, and the pharmaceutical composition of the present invention may be used in combination with such treatment.

The duration of treatment with the pharmaceutical composition of the present invention and the duration of treatment for other interstitial pneumonia may or may not overlap, but they are preferred.

The pharmaceutical composition of the present invention may be used in combination with alkalizing therapy. As used herein, alkalizing therapy refers to raising the pH of urine.

Drugs that increase the pH of urine are known, and examples thereof include, but are not limited to, sodium hydrogen carbonate, sodium carbonate, calcium carbonate, sodium citrate, potassium citrate, and the like. Ularit® is a typical preparation that raises the pH of urine. The type, administration route, dose, etc. of these drugs can be appropriately selected and determined by the doctor.

In the present invention, it is preferable to raise the pH of the patient's urine by 1 or more, more preferably 1.2 or more, and 1.5 or more by the alkalizing therapy as compared with before the start of the alkalizing therapy. More preferred. The increase in urine pH due to alkalization therapy is determined by the pH of urine after a certain period of time (for example, 1 month, 3 months, 6 months or 1 year) after the start of alkalinization therapy, and before the start of alkalization therapy. It may be evaluated by comparing the pH of urine. The value of urine pH may be, for example, the average value of urine pH for several days or weeks.

The combination of the pharmaceutical composition of the present invention with alkalizing therapy may be as follows. It is preferable that the administration period of the pharmaceutical composition of the present invention and the period of alkalizing therapy overlap. For example, when the administration period of the pharmaceutical composition of the present invention is one year, the period of alkalizing therapy may be one year, one year or more, or one year or less. It is preferable to continue the alkalizing therapy during the administration period of the pharmaceutical composition of the present invention. The pharmaceutical composition of the present invention may contain an agent that raises the pH of urine.

The present invention provides, in another embodiment, an adjunct to the treatment of interstitial pneumonia, which comprises vitamin C and / or its derivatives. As used herein, the therapeutic aid for interstitial pneumonia is to enhance the effect of a therapeutic agent for interstitial pneumonia and / or to the effect of a therapeutic agent for interstitial pneumonia for interstitial pneumonia due to vitamin C. It means adding a therapeutic effect. The therapeutic effect of interstitial pneumonia can be determined by a known method, and may be determined by examining, for example, an X-ray photograph, a CT image, or a marker such as KL-6 or SP-D.

Examples of vitamin C derivatives that may be contained in the therapeutic aid of the present invention include the same vitamin C derivatives that may be contained in the pharmaceutical composition of the present invention. The dose, administration route, administration period, administration frequency, production, prescription, etc. of the therapeutic aid of the present invention may be similar to the pharmaceutical composition of the present invention, depending on the type of treatment for interstitial pneumonia. You may decide.

The therapeutic aid of the present invention can be produced by using known means and methods. Typically, the therapeutic aids of the invention are formulated with known carriers similar to those described for the pharmaceutical compositions of the invention.

The therapeutic aids of the present invention can assist in the treatment of any type of interstitial pneumonia. Treatments for interstitial pneumonia include drug therapies such as steroids, immunosuppressants, and antifibrotic agents (eg, pirfenidone, nintedanib); oxygen therapy; respiratory rehabilitation; lung transplantation. However, it is not limited to these treatments. In the case of secondary interstitial pneumonia, the therapeutic aids of the present invention may be used to assist in treatment to eliminate the cause.

The period of assistance for treatment using the therapeutic aid of the present invention and the period of treatment for interstitial pneumonia may or may not overlap, but it is preferable that they overlap.

The therapeutic aid of the present invention may be used in combination with alkalizing therapy. The alkalizing therapy and the combination with the alkalizing therapy are as described above.

The therapeutic outcome can be improved by using the pharmaceutical composition of the present invention in combination with the treatment of other interstitial pneumonia, or by assisting the treatment of interstitial pneumonia with the therapeutic aid of the present invention. It can reduce the side effects of other treatments for interstitial pneumonia.

The present invention provides, in a further aspect, the use of vitamin C or a derivative thereof for the treatment of interstitial pneumonia. The use may be combined with alkalizing therapy.

The present invention provides, in a further aspect, the use of vitamin C or a derivative thereof to assist in the treatment of interstitial pneumonia. The use may be combined with alkalizing therapy.

In a further aspect, the present invention provides the use of vitamin C or a derivative thereof in the manufacture of a therapeutic agent for interstitial pneumonia. The drug may be used in combination with alkalizing therapy.

The present invention provides, in a further aspect, the use of vitamin C or its derivatives in the manufacture of therapeutic aids for interstitial pneumonia. The therapeutic aid may be used in combination with alkalizing therapy.

The present invention provides, in a further aspect, a method of treating interstitial pneumonia in a subject requiring treatment of interstitial pneumonia, characterized in that vitamin C or a derivative thereof is administered to the subject. The treatment method may be performed in combination with alkalizing therapy.

The present invention, in a further aspect, is a method of assisting the treatment of interstitial pneumonia in a subject requiring assistance in the treatment of interstitial pneumonia, characterized in that vitamin C or a derivative thereof is administered to the subject. I will provide a. The therapeutic aid may be performed in combination with alkalizing therapy.

Hereinafter, the present invention will be described in more detail and concretely with reference to Examples, but the Examples do not limit the scope of the present invention.

Patients with interstitial pneumonia (female, 60s)
The patient underwent lung cancer surgery in 1998. In 2005, he was pointed out to have a recurrence and underwent surgery. He was pointed out to have a recurrence in 2006, but refused surgery. From 2006 to January 2015, she was taking Iressa, then Tarceva until June 2020, and then Geotrif.
The patient was diagnosed with interstitial pneumonia around May 2011.
Since 2011, 25 g of vitamin C has been infused once a month, but when KL-6 increased around January 2019 and then increased to 25 g of vitamin C once a week, KL-6 decreased and interstitial. Improvement of pneumonia was shown (Fig. 1).

Patients with interstitial pneumonia (male, 60s)
He was diagnosed with interstitial pneumonia around 2015. Started taking pirfenidone (Piresupa) in April 2020. In February 2020, primary lung cancer was suspected during follow-up of interstitial pneumonia, and surgery was performed in May 2020. Based on the pathological results, the patient was diagnosed with lung adenocarcinoma pstage I and small cell lung cancer pstage I.
Alkaline therapy (alkaline diet, baking soda, and uralit) was started on March 11, 2020, and weekly vitamin C (25 g / dose) infusion was started on March 12, 2020.
KL-6 decreased about 1 month after the start of vitamin C infusion, and continued to decrease thereafter (Fig. 2). SP-D also shows a downward trend after the start of vitamin C infusion (Fig. 2). From these results, improvement of interstitial pneumonia was shown (Fig. 2).

Patients with interstitial pneumonia (female, 80s)
The time of diagnosis of interstitial pneumonia is unknown, but there was an interstitial shadow from the time of diagnosis of appendix cancer. After that, only follow-up was performed. He was diagnosed with appendix cancer in September 2015 and underwent surgery on September 30.
Alkaline therapy (alkaline diet and baking soda) was started on November 30, 2015, and vitamin C infusion (25 g / dose once or twice a month) was started in January 2017, both of which are ongoing.
The transition of KL-6 and SP-D from October 22nd to November 17th, 2020 is shown in FIG. Both decreased, indicating improvement in interstitial pneumonia. In addition, after the start of alkalization therapy and vitamin C infusion, the urine pH increased and then maintained at 7-8 (data not shown). The N / L ratio also decreased after the start of alkalization therapy and vitamin C infusion, and although a temporary increase was seen around November 2018, it has remained between about 3 and 4 (data not shown). FIG. 4 shows a chest CT photograph taken over time before and after the start of vitamin C infusion. It can be seen from FIG. 4 that interstitial pneumonia has hardly progressed since the start of vitamin C infusion in January 2017.

Patients with interstitial pneumonia (male, 80s)
CDDP + GEM therapy was performed from August 25, 2011, and radiation therapy (30 times) was performed from January 18, 2012. Vitamin C infusion was performed from January 2014 (frequency and continuation are unknown). In October 2018, he was hospitalized with pneumothorax and was diagnosed with interstitial pneumonia. After that, MRSA pneumonia developed. He underwent lumbar spine surgery between March 2019 and April 2020. At that time, it was considered that the exacerbation of interstitial pneumonia occurred because pure oxygen inhalation was performed for a certain period of time. Vitamin C infusion (35 grams / week) was resumed and continued from August 3, 2020.
The transition of KL-6 and SP-D (August 20, 2020 to October 20, 2020) after the resumption of vitamin C infusion is shown in FIG. Both KL-6 and SP-D decreased, indicating improvement in interstitial pneumonia.
A chest X-ray photograph before and after the resumption of vitamin C infusion is shown in FIG. The disappearance of the interstitial shadow was observed after the infusion of vitamin C. A chest CT photograph before and after the resumption of vitamin C infusion is shown in FIG. The disappearance of the honeycomb-like shadow was observed after the infusion of vitamin C. From these photographs, the therapeutic effect of vitamin C on interstitial pneumonia was confirmed.

The present invention is available in the field of pharmaceuticals, especially in the field of therapeutic agents for interstitial pneumonia.

Claims (4)

A pharmaceutical composition containing vitamin C for treating interstitial pneumonia, wherein a dose of 25 g or more of vitamin C is administered at least once every two weeks. The pharmaceutical composition according to claim 1, which is used in combination with alkalizing therapy. An adjunct to the treatment of interstitial pneumonia, which contains vitamin C, and a dose of 25 g or more of vitamin C is administered at least once every two weeks. The agent according to claim 3, which is used in combination with alkalizing therapy.

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