# US 10,765,751 B2 · pH sensitive carrier and preparation method thereof, and pH sensitive drug and pH sensitive drug composition each containing the carrier, and method for treating or preventing diseases using the same

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- Number: US 10,765,751 B2
- Document ID: US10765751B2
- Status: Granted
- Kind: B2
- Application number: 15/816,513
- Filed: 2017-11-17
- Published: 2018-04-19
- Granted: 2020-09-08
- Earliest claimed: 2012-05-31
- Assignees: Terumo Kabushiki Kaisha
- Applicants: Terumo Kabushiki Kaisha
- Inventors: Naoki Sakaguchi
- Web page: https://patentgrep.com/patent/US10765751B2

## CPC

- A61K 47/24: containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
- A61K 9/1075: {Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence)}
- A61K 9/1272: comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers (lipids as modifying agents {A61K47/543})
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 38/02: Peptides of undefined number of amino acids; Derivatives thereof
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/14: Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
- A61K 47/28: Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

A method for treating tumor or inflammation in a patient in need thereof by administering a pH sensitive drug which includes a pH sensitive carrier including at least one amphipathic substance, and a physiologically active substance supported in the pH sensitive carrier to induce the pH sensitive carrier to develop a membrane disruptive function and to deliver the physiologically active substance to the site. The pH sensitive carrier can include at least one of deoxycholic acid, cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, C27 bile acid, glycodeoxycholic acid, glycyrrhizic acid, glycyrrhetinic acid and salts thereof, and the amphipathic substance can include at least one of a phosphatidylcholine having 10 to 12 carbon atoms, a polyoxyethylene sorbitan monofatty acid ester having 12 to 18 carbon atoms, a sorbitan fatty acid ester having 16 to 18 carbon atoms, glycerol monooleate, glycerol dilaurate, glycerol distearate, glycerol dioleate, polyoxyethylene castor oil and α-tocopherol.

## Claims

### Claim 1

A method for treating tumor or inflammation in a patient in need thereof which comprises:
administering a pH sensitive drug which comprises a pH sensitive carrier which comprises at least one amphipathic substance, and a physiologically active substance supported in the pH sensitive carrier to induce the pH sensitive carrier to develop a membrane disruptive function and to deliver the physiologically active substance to the site,
said pH sensitive carrier including at least one pH sensitive compound selected from the group consisting of deoxycholic acid, cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, C27 bile acid, glycodeoxycholic acid, glycyrrhizic acid, glycyrrhetinic acid and salts thereof, and said at least one amphipathic substance being at least one selected from the group consisting of a phosphatidylcholine having 10 to 12 carbon atoms, a polyoxyethylene sorbitan monofatty acid ester having 12 to 18 carbon atoms, a sorbitan fatty acid ester having 16 to 18 carbon atoms, glycerol monooleate, glycerol dilaurate, glycerol distearate, glycerol dioleate, polyoxyethylene castor oil and α-tocopherol, and is capable of developing a membrane disruptive function promoting effect, and
the pH sensitive compound being present in an amount not less than 10 moles per 100 moles of the amphipathic substance.

### Claim 2 (depends on 1)

The method as defined in claim 1, wherein the pH sensitive compound and the amphipathic substance form micellar particles.

### Claim 3 (depends on 2)

The method as defined in claim 2, wherein the particle size is 10 to 200 nm.

### Claim 4 (depends on 1)

The method as defined in claim 1, wherein when a leakage of the pH sensitive compound alone in a leaching test is taken as La, a leakage of the amphipathic substance alone taken as Lb, a leakage of the pH sensitive carrier taken as Lc, leakages at a pH of 7.4, respectively, taken as Lc7.4, La7.4 and Lb7.4, and leakages at a pH of 5.0 or 4.5, respectively, taken as Lcx, Lax and Lbx, Δ represented by the following formula (1) is not smaller than 5 and Δ′ represented by the following formula (2) is not smaller than 5:
Δ=(Lcx−Lc7.4)−(Lax−La7.4) Equation (1)
Δ′=Lcx−(Lax+Lbx) Equation (2).

### Claim 5 (depends on 1)

The method as defined in claim 1, wherein the physiologically active substance is made of a protein or peptide.

### Claim 6

A method for treating tumor or inflammation in a patient in need thereof which comprises:
administering a pH sensitive drug composition which comprises a pH sensitive carrier which comprises at least one amphipathic substance, and a physiologically active substance to induce the pH sensitive carrier to develop a membrane disruptive function and to deliver the physiologically active substance to the site,
said pH sensitive carrier including at least one pH sensitive compound selected from the group consisting of deoxycholic acid, cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, C27 bile acid, glycodeoxycholic acid, glycyrrhizic acid, glycyrrhetinic acid and salts thereof, and said at least one amphipathic substance being at least one selected from the group consisting of a phosphatidylcholine having 10 to 12 carbon atoms, a polyoxyethylene sorbitan monofatty acid ester having 12 to 18 carbon atoms, a sorbitan fatty acid ester having 16 to 18 carbon atoms, glycerol monooleate, glycerol dilaurate, glycerol distearate, glycerol dioleate, polyoxyethylene castor oil and α-tocopherol, and is capable of developing a membrane disruptive function promoting effect, and
the pH sensitive compound being present in an amount not less than 10 moles per 100 moles of the amphipathic substance.

### Claim 7 (depends on 6)

The method as defined in claim 6, wherein the pH sensitive compound and the amphipathic substance form micellar particles.

### Claim 8 (depends on 7)

The method as defined in claim 7, wherein the particle size is 10 to 200 nm.

### Claim 9 (depends on 6)

The method as defined in claim 6, wherein when a leakage of the pH sensitive compound alone in a leaching test is taken as La, a leakage of the amphipathic substance alone taken as Lb, a leakage of the pH sensitive carrier taken as Lc, leakages at a pH of 7.4, respectively, taken as Lc7.4, La7.4 and Lb7.4, and leakages at a pH of 5.0 or 4.5, respectively, taken as Lcx, Lax and Lbx, Δ represented by the following formula (1) is not smaller than 5 and Δ′ represented by the following formula (2) is not smaller than 5:
Δ=(Lcx−Lc7.4)−(Lax−La7.4) Equation (1)
Δ′=Lcx−(Lax+Lbx) Equation (2).

### Claim 10 (depends on 6)

The method as defined in claim 6, wherein the physiologically active substance is made of a protein or peptide.