TWI306030B - New self emulsifying drug delivery system - Google Patents

Description

1306030 A7 B7 V. INSTRUCTION DESCRIPTION (1) The present invention relates to a novel pharmaceutical composition in the form of a pre-concentrate emulsion, a unit dosage form containing the composition, its use in medicine, and a preparation method thereof . Background and Prior Art Non-steroidal anti-inflammatory drugs, generally known as NsAIDs, are conventional drugs for the treatment of pain and inflammation. One of the major drawbacks of NSAIDs is that they have severe gastrointestinal side effects. Patients who take NS AIDs (like naproxen) for a long time during treatment often experience problems with gastrointestinal side effects. Recently, it has been found that the release of nitric oxide NS AID compounds (hereinafter referred to as NS AIDs which can release NO) has an effect of improving side effects, see, for example, w〇94/04484, W0 94/12463, W0 95/0983 1 and W0 95. /30641. The NS AIDs from which NO can be released are lipophilic compounds with poor water solubility. According to the biomedical classification system proposed by Amidon et al. (pharm Res 12 (1995), pp. 413-420), they can be classified as Category 2. Such drugs are characterized by low water solubility but with adequate permeability. A problem in biomedicine of these compounds is that the absorption of their gastrointestinal tract (GIT) is limited by the rate of dissolution, resulting in poor bioavailability once administered orally. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative WO 95/08983 discloses a self-emulsifying composition for oral administration which forms a microemulsion in situ when contacted with a biological fluid. The composition may be characterized by its self-microemulsifying drug delivery system (SMEDDS) and comprising at least one active compound, - a lipophilic phase consisting of a mixture of glycerides and fatty acid esters. Standard (CNS) A4^iT(2^'x 297l>« ) 1306030

1306030

V. Description of the invention (Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs, the emulsion is much larger than the wood complex, and its diameter is from nanometer to micrometer. The emulsion is usually a two-phase system, which is thermodynamically unstable (but dynamically stable) The other major difference between the composition of ΕΡ 274 870 and the composition of the present invention is the nature of the active compound. The NSAIDs are essentially crystalline powders, but the NSAIDs that can be used to release NO or the NSAIDs that can release NO are used in the present invention. The mixture is an oily or heat softenable semi-solid. Furthermore, the micelles require a higher ratio of surfactant to surfactant than the surfactant: surfactant ratio: the ratio of surfactants. One of the unique features of NSAIDs is that many of these compounds are oily or heat softenable semi-solids that are practically insoluble in water. Use high doses of NSAIDs that release NO, for example, at doses above about 350 mg. It is not easy to formulate large quantities of oil or semi-solid tablets of reasonable size. However, the NSAIDs which release lipophilic NO can be formulated into an oil-in-water emulsion, wherein the compound constitutes the oil. The phase is either part of the oil phase, which is emulsified in water by one or more surfactants. In the pharmacokinetic study of animals, the NS that can release N 〇 is found. The bioavailability of AID s oil-in-water emulsions is much better than that of unemulsified materials. However, the problem with such emulsions is that they are thermodynamically unstable, and long-term storage stability is extremely poor because they are easy to combine. In the form of emulsion/deposition or phase separation. Further, it does not represent a suitable dosage form for oral administration, because it is usually necessary to put a large volume into a certain dose, which is unpleasant bitter or fat-like. The taste is a problem. In particular, it is not possible to fill an oil-in-water emulsion into a gelatin capsule because the large amount of water in the emulsion is incompatible with the outer shell of the capsule and it is highly likely to dissolve it. Standard (CNS) A4 specification (210 X 297 public) ----------Install·!---- I Book·---I--- (Please read the notes on the back and fill in This page) 1306030 A7 B7 V. INSTRUCTIONS (4) Brief description of the present invention. The problem has now been solved by providing a new self-medicating drug delivery system (generally known as SEDDS) suitable for oral administration. The present invention is more specific to a pharmaceutical composition suitable for oral administration. The preconcentrate emulsion is in the form of (1) one or more NSAIDs that release NO; (ii) one or more surfactants; (in) an oil fat or semi-solid fat, as the case may be; When the medium (such as a gastrointestinal fluid) is contacted, an oil-in-water emulsion is formed in situ. The composition according to the present invention may further comprise one or more short-chain alcohols. The composition of the child may be in contact with the gastrointestinal fluid. Forming an oil-in-water emulsion in the form of a nanometer to micron droplet, the droplet consisting of one or more NSAIDs that form N0, which forms the core of the droplet, the droplet The core is covered by - or a multi-layer surfactant. The oil-in-water emulsion formed in situ will provide an NSAID capable of releasing NO with excellent bioavailability once administered orally. The storage stability of the emulsion is not one of the considerations, because the ritual liquid will not form until the preconcentrate is ingested by the patient, that is to say, there will be no emulsion shape at the beginning of the second administration. When the preconcentrate is filled into the capsule, it may have an unpleasant bitter taste which is not a big problem. The pharmaceutical composition according to the present invention is a preconcentrate at the time of administration to the patient. The pre-concentrate emulsion can be filled into a single unit dosage form, such as a capsule 'drinking ampoule and a dose pad' or otherwise may be in other suitable dosage forms. -----------7- The paper scale applies to the Chinese National Standard (CNS) A4 specification (2) 297 297 public love 13〇6〇3〇

V. Description of the invention (5 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives printed, 'like chewable soft pills, and chewable tablets. Once in contact with aqueous media (like gastrointestinal fluids), this preconcentrate The emulsion will be converted into an oil-in-water emulsion. Therefore, the composition will form an oil-in-water emulsion in the gastrointestinal tract (GI 迢). The release rate of the composition will depend on the droplets formed in the original emulsion. The size of the liquid and the polarity of the emulsion droplets, which are perceived in the hydrophilic/lipophilic equilibrium state (HLB)' of the agent/surfactant mixture and the concentration of the surfactant. Too large, small size and high polarity Drops can result in high rates of drug release (NH, Shah et al., int. J. Pharm. 106 (1994), pp. 15-23). NSAIDs are non-steroidal anti-inflammatory drugs, that is, any Anti-inflammatory effect, but this compound does not belong to the category of "steroids. Those familiar with the art are aware of whether a compound is within the definition of NSAID. Specific examples of NSAIDs are naproxen, dicl〇fenac, aceci〇fenac, indometha Cine,ketorolac' sulindac,meloxicam,piroxicam,tenoxicam,ibuprofen,ketoprofen,naproxen,azapropazon,nabumeton »carprofen,tiaprofenic acid,suprofen,indoprofen 'etodolac,fenoprofen,fenbufen,flurbiprofen ' bermoprofen ' pirazolac,zaltoprofen,nabumetone,bromfenac' ampiroxicam , and lornoxicam. In any case, this list should not be considered as a depletion. The 'NS AID that can release NO' is intended to include all non-steroidal anti-inflammatory drugs (NSAIDs), their salt or mirror image isomerism. The substance has the potential to release nitrogen oxides. The NS AIDs that release NO are lipophilic compounds with poor water solubility. According to the biomedical classification system proposed by Amidon et al. (Pharm. Res. -8 - this paper scale applies to China) National Standard (CNS) A4 Specification (210 X 297 mm) -----------i II K----Order--------Thai (Please read the notes on the back first) Fill in this page again) 1306030 A7 B7 Jade, Inventions (6) 12 (1995), pp. 413-420), which can be classified as Category 2. These drugs are characterized by low water solubility, but with appropriate permeability. The biomedical problem of these compounds is that the absorption of their gastrointestinal tract (GIT) is limited by the rate of dissolution, resulting in poor oral administration once administered orally. Bioavailability. NS AIDS, which preferably releases NO according to the present invention, is a compound of formula I 〇

II MC-0-X-ONO, where X is a spacer 'that is a compound that forms a bridge between the nitrogen oxide supply group and the NS AID; and the lanthanide is selected from C. Please read the back of the note first. Please fill out this page again)

CI

CI CH;

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

-9- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1306030 A7 V. Invention description ( α Β 7

XT

C

Ch3o

OzΛ

In a preferred embodiment of the Ministry of Economic Affairs, the Intellectual Property Office, the Consumer Cooperatives, and the preferred embodiment of the present invention, the ''branched or ring-shaped extension base' (CH2K is selected from the group consisting of ^-line and -(CH2)m-〇- (CH2)p-, Lizhong.''Integer of ljl0; -CH2-PW...<> and ... to 1. The whole of the two---- in the specific embodiment, the horse activity in the SEDDS formula according to the present invention The NS AIDS system of the compound which is capable of releasing N0 is disclosed and claimed in WO 94/04484 - WO 94/12463 > WO 95/0983 1 #b WO 9 5/30641, the disclosure of which is incorporated herein by reference. This paper size is applicable to China National Standard (CNS) A4 specification (21〇x 297 mm). h---订----- I — . (Please read the notes on the back and fill out this page)

1306030 A7 B7 V. INSTRUCTIONS (8) NS AIDs suitable for the specific release of NO according to the present invention are

CH.O

ΟΝΟ 2 (la)

〇N〇? (lb)

ΟΝΟ, (Id) CH,

〇N〇, (10) ---------------- „-订--------▲ (Please read the phonetic on the back? Please fill out this page again)

ΟΝΟ, (le) Printed by the Consumers’ Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

ΟΝΟ, (If) -11 - This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1306030 A7 B7 V. Description of invention (9) 〇,

,〇N0o (ig)

ΟΝΟ 2 (Ιί)

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ----------------r---book-------- (please Read the precautions on the back and fill out this page.) 1306030 A7 B7 V. INSTRUCTIONS (10)

Me〇

Cl o^^ono2 (In)

MeO

ONO, (l〇) ----------装-----„----订---- (Please read the notes on the back and fill out this page)

MeO

〇N〇2 (Ip); and the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

Cl 0, Όνο, (lq) 13 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1306030 A7 V. Invention Description (U) p-::1: This 2 Series King Powder Shape' However, the NSAIDs of N0 can be released (please read the note on the back and fill out this page): You should be able to provide - semi-solid or oily compounds. The advantage of this unique feature is that the blood needs to be pre-sprinkled. Hq. The mountain is at this time, and any exotic lipophilic oil or any semi-solid energy is added to the pre/chen fine emulsion, because this is a potion - innate, A pharmacologically inert oil or semi-solid lipopeptide Λσ Λ ψ敕一木王工马心月曰 fat can be added to the pharmaceutical composition through a filler or a viscosity modifier. For low doses, no The dosage system is required to increase the accuracy of the dosage. The viscosity modifier is used to: = the optimum viscosity of the composition to be filled into the capsule, for example. At the speed of the end, the capsule must be carefully filled with liquid. Control its viscosity to avoid f hair + touch at low viscosity limit; Ό, π 1 , t especially poor sputum splash situation and In the range of avoiding the formation of filaments at high viscosity limits, the viscosity must be selected to form an audible formula. The viscosity required to fill the liquid in the capsule is generally in the range of 0.1 to 25 Pa S. The total amount of NSAID (1) for releasing NO used in the present invention is preferably MM 500 mg per unit dose. Further, in a preferred embodiment, the amount of the rib (4) which can be released in the composition of the child is Contains 125-500 mg per unit dose. Ministry of Economic Affairs Intellectual Property Office Employees Consumption Cooperatives Printing Units F Division I Division is defined as the amount of active compound administered in a single capsule, or the active compound dissolved in a glass of water. "Interacting Agent" is defined as a surface-active amphiphilic compound, such as a quinone copolymer. The preferred surfactant according to the present invention is a nonionic surfactant, for example, containing polyethylene. Glycol (PEG) chains, especially block copolymers like poloxamers. Examples of suitable Poloxamers are Poloxamer 407 (Pluronic 14- This paper scale applies to China National Standard (CNS) A4 specification (210 x 297) Chu) 1306030 A7 __B7_ V. Description of invention (12) F127®); Poloxamer 401 (Pluronic L121®); Poloxamer 237 (Pluronic F87®); Poloxamer 33 8 (Pluronic F138®); Poloxamer 331 (Pluronic L101®); Poloxamer 231 (Pluronic L81®); a tetrafunctional polyoxyethylene polyoxybutylene block copolymer known as Poloxamine 908 (Tetronic 908®); Pol〇xamine 1307 (Tetronic 1307®); Poloxamine 1107 Polyoxyethylene polyoxybutylene segmented copolymer, known as Polyglycol BM45®. The exemplified surfactants are not intended to be used in the present invention, and the present invention is not to be considered as exhaustive and should not be construed as limiting the invention. All of the above surfactants are commercially available from, for example, BASF, D〇w Chemicals, and Gattefoss 6. According to the present invention, the total amount of the surfactant ranges from 12.5 to 6 mg, preferably from 100 to 500 mg. The NSAID at which NO can be released: the ratio of the surfactant is 丨: 0 '丨 to 丨: ι〇' is preferably 1: 0.3 to 1: 3. Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed If an additional oil is added to the pharmaceutical composition, it can be any oil as long as it is inert and compatible with the capsule material, and is acceptable for use with the drug. . Those skilled in the art should understand what should be chosen: oil to achieve the intended purpose. Examples of suitable oils which can be used in the present invention are vegetable oils such as scorpion oil, corn oil, soybean oil, rapeseed oil, safflower oil, and cannabis oil. Animal oils, such as fish oil and triglycerides, are suitable for use in the present invention. Combination: semi-solid fat is used as a filler, and (4) is selected from the group consisting of early-, mono- and diglycerides, and fatty acid alcohols.

Gelucires 33/01®, 39/01®, 43/01®, we paralyze the alcohol, 'palm stearin, like -15' This paper scale thorns close the home (CNS) A4 specifications (2) 297 297 public) I3〇6〇3〇5, invention description (13 is Μ*01 ΑΤ〇5@.^^ is a single glycerin mixed _, two knows the purpose of 1PEG single H or free coffee Mixture—., 二可钟Γ明 (In the wood level, an oily (lipophilic) or semi-solid NSAID that can release NO is used as an active ingredient. U According to this January long drug composition uses extra For oil control, it can be used as a filler or a viscosity modifier. 9 1 "Short chain alcohol" used in the present invention is defined as a single carbon having a carbon atom = shape or a branch shape. Or triol. Examples of suitable (iv) short-chain alcohols are ethanol, propylene glycol and glycerol. If 29 a short-chain alcohol is added to a pharmaceutical composition according to the invention, it can increase the degree of bathing and the amount of surfactant required. In another aspect of the invention, two or more types of releasable NO^ NSAIDs are used as active ingredients, and all of the agents herein may be oil or solid. The type exists, or at least one of the agents is present in an oil or semi-solid form. 'Others are present in a solid form that is soluble or suspended, oil or semi-solid compound. If high doses are low, N〇 can be released. The milk is fine to the NO, and it is hoped that the low-dose high-efficiency energy can be released. The combination of two or more kinds of n_nsaiDs is beneficial.

Addition of a half-filler Another aspect of the invention is the incorporation of one or more NSNs that release N〇 and a proton pump inhibitor (ΡΡΙ) κ complex that is susceptible to acid. N0_NSAIDs should be formulated into an emulsified part of the stomach, that is, the SEDDS formulation as described above. At the same time, the proton pump inhibitor (ρρι) which is susceptible to acid must be protected from acidic gastric juice by, for example, coating through the casing. . The casing layer ppI is always up to 16- This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (21〇X 297 public ^ 1306030 A7 B7 5. The invention description (14) will change when it arrives in the intestine. PPI. The casing coating unit of each prepared proton pump inhibitor can be mixed into the SEDDS melt. Alternatively, the PPI can be filled into a capsule filled with solidified SEDDS, and the SEDDS and the prepared PPI pill are required. There is a layer of protective paraffin. In another embodiment, the PPI pellets produced can be mixed into a liquid SEDDS formulation. This combination can thus be in a fixed form, that is, an NSAID that is capable of releasing NO first ( s) and a proton pump inhibitor susceptible to acid, which is then filled into a suitable dosage unit. In another embodiment of the invention, a proton pump inhibitor susceptible to acidity can be filled in NSAID(s) containing one or more releasable oximes in capsules in a cured SEDDS formulation - in this case, there is a need for a protective layer between the SEDDS formulation and the acid-affecting proton pump inhibitor Paraffin or other inert substance. In a specific embodiment, a proton pump inhibitor susceptible to acid is mixed into a liquid SEDDS formulation that releases NSAID(s) of NO. One of the alternatives of the present invention, the NSAID of the NO that can be released (s) and PPI can be provided in the form of a set, where the NS AID and PPI of NO can be continuously administered, that is, one after another. The order of administration is not so significant, this means One of the NS AIDs and PPIs from which NO can be released can be administered before another. Accordingly, one embodiment of the present invention comprises a combination therapy in which one or more NS AIDs that can release NO are administered. Such a treated patient, followed by administration of PPI, and vice versa. As mentioned above, an example of a proton pump inhibitor suitable for administration in combination with an NSAID capable of releasing NO according to the present invention is a compound of formula I or a pharmaceutically acceptable compound thereof. -17 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the note on the back of the page and then fill out this page) -----r---book.-- -----

Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1306030 A7B7 V. Description of Invention (15) Tested salt, or one of its single-mirror isomers or the salt of the single-mirror isomer: 〇Het "X-S- He% I where HetA IHet2 is

<Please read the notes on the back and fill out this page.)

Or R8

n· ^ I n - Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed - CH - R11 | Latch 10 or \ η r12 -18- This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1306030 A7 -----~- B7 _________ V. Inventive Note (16) where - ·, 'N in the phenylimidazole moiety represents one of the carbon atoms substituted by hR·9, as shown without any substitution The nitrogen atom of the group is substituted; R, 'the ruler 2 and R3 are the same or different, and are selected from the group consisting of hydrogen, a group, an alkoxy group, as the case sinks fluorine, alkyl sulfur, alkoxy alkoxy, dioxane Substituted with an amine group, an acridinyl group, a morpholinyl group, a phenyl group, a phenyl group and a phenylalkoxy group; R4 and Rs are the same or different and are selected from hydrogen, an alkyl group and an aryl group; R6' is hydrogen 'Alizarin, trifluoromethyl, alkyl and alkoxy;

Re-R9 is the same or different and is selected from the group consisting of hydrogen, alkyl, alkoxy, a functional group, a halogenated oxy group, a oxycarbonyl group. Sitting base, three chaotic bases, 'or adjacent R6-R_9 form a ring structure that can be further replaced; R1 〇 is hydrogen or is flush with R_3 to form a stretch chain, and Rn and R!2 are the same Or different, and is selected from hydrogen, halogen or alkaloid, alkoxy which can be branched or straight (^-(^9-chain or contains a cycloalkyl group, such as a ring-based group) An example of a specific proton recording inhibitor suitable for use in accordance with the present invention is (please read the notes on the back and then fill out this page)

---,J· i n n Bn Ik i I Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

ο 1 s Λ

3 Η

Omeprazole This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1306030 Α7 Β7 V. Invention description (17)

II N-

Lansoprazole

Η OC OCHF, II Ν--

S Η

Pantoprazole

Pariprazole Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Η -20- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1306030 A7 B7 V. Invention Description (18)

Leminoprazole

----------Install-----r---订--------Win (please read the phonetic on the back? Please fill out this page again) Ministry of Economic Affairs Intellectual Property Office staff Printed by consumer cooperatives

-21 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 191306030 1. Invention description (〇CH,

Μ 八 ^ N 'CH2—S—f H OCH,

The Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative prints the use of the acid-affected proton pump used in the dosage form of the invention in the form of a neutral or a test salt, such as heart +, Μ, he /, K+ or 軚Good for Mg2+ salt. Further, where appropriate, the above-mentioned J + s species may be used in the form of a pure mirror image isomer or a salt of a single mirror isomer. Suitable inhibitors are disclosed, for example, in EP-A1-0005 129, A1 174 726, EP-A 1-166 287, GB 2 163 747 and WO 90/06925, and particularly suitable compounds are disclosed in 95/〇1 977 and WO 94/27988. The proton pump inhibitor used in the combination according to the invention is preferably a pellet comprising a casing coating which is susceptible to acid-affected proton pump inhibitors. For the casing coating pill composition, reference is made to WO 96/01623, which is incorporated herein by reference. Preparations can be such as ---------- Λ9 Μ--------- order--------1 (please read the notes on the back and fill out this page) -22 - This paper scale applies to China National Standard (CNS) A4 specification (21〇χ 7 mm) 1306030 A7 V. Invention description (20)

Suitable combinations according to the invention are, for example, the NS AID of the formula 1 & and the test salt of omeprazole or omeprazole, the alkali salt of (s)-omeprazole or (S)-omeprazole; or the releaseable NO of the formula π An alkali salt of NSAID and omeprazole or omeprazole, an alkali salt of (s)_mepraz〇le or (S)-omeprazole, the pharmaceutical composition of the present invention is filled into a single dosage form suitable for oral administration, such as Capsules, drinking ampoules and dose pads, or may be formulated into other suitable oral dosage forms, such as chewable soft pills and non-chewable tablets. In a preferred embodiment of the present invention, the pharmaceutical composition is colonized into a hard gelatin capsule, but other alternative materials such as a methylcellulose-based outer shell may be used and may be used. Soft gelatin capsules. In another embodiment of the invention, the pharmaceutical composition is, for example, soluble in a cup of water, thereby allowing the preconcentrate to be converted into a soft gelatin capsule by a composition intended for dissolution prior to administration. It is especially advantageous for a patient who has difficulty in appeasement and a composition of the same agent for pediatric patients with plastic or glazed mats. In a preferred embodiment, it will be in the capsule. The preferred capsule "„^" == composition filled into the rubber capsule consists of two parts of the -cap and the body, the inside of part a. The hard gelatin capsules produced are in the middle of the second, in another - It is a capsule that is completed during the operation of another step - 酽 φ, 佳~ ^ ^ '% 充 充 . . . . . . . . . . . . . . .

As mentioned above, the Ministry of Economic Affairs, the Intellectual Property Office, the employee consumption cooperative printed 1306030 ~ top very shrinking emulsion once 盥w an oil-in-water emulsion, thereby releasing the active drug. Because: contact will become an oil-in-water emulsion that will form in the gastrointestinal tract (GI tract); the pharmaceutical composition of the present invention is especially suitable for treating pain and hair. "B) is intended to contain 'but not Limited to the feeling of injury # pain: pain or its combined pain; acute, intermittent or chronic pain; tumor: pain similar to the origin of migraine and headache. "Inflammation" word is intended to cover this y shower, rheumatism关 inflammation; osteoarthritis; and juvenile inflammation D, but not limited to preparation method The pharmaceutical composition of the present invention can be made by the following alternative methods. I. Mixing a) Oily or semi-solid releaseable NO The NSAID is placed in a crying, adding solid or semi-solid surfactant and solid/oily fat: non. Mandatory: ). The mixture is heated to a temperature equivalent to the melting point of the excipient to prepare a fluid formulation which is thoroughly mixed until homogeneous (by visual inspection) and = the preconcentrate is filled in a capsule suitable for oral administration. b) Alternatively, the NSAID of the oily release NO is placed in a container and the fluid surfactant is added. The mixture is thoroughly mixed until it is homogeneous (by visual inspection) and the preconcentrate is filled in a capsule suitable for oral administration. c) In another alternative method, the NS AID of the oily releaseable NO is placed in a container and the solid surfactant (particle size < 17 7 microns) ground into a fine powder is added. Mix the mixture thoroughly until it is homogeneous (by visual inspection) and fill the pre-concentrate in capsules suitable for oral administration. 24- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm).

1306030

V. Description of invention (22 Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Employees' Consumption Cooperatives ο d) In the alternative: in the alternative method, the semi-solid/solid surfactant is placed in a valley, and added - or multiple Alcohol. The mixture is heated to a temperature at which the phase S is at the melting point of the excipient, and a fluid formulation is prepared which is thoroughly mixed until uniform (inspected by inspection). Add N0_NSAID and mix the mixture thoroughly until uniform (by visual inspection). The preconcentrate is filled in a capsule suitable for oral administration. e) In yet another alternative, a liquid surfactant is placed in the device and one or more alcohols are added. The mixture is thoroughly blended until it is homogeneous (inspected by visual inspection). Add N〇_NSAID and mix well until the mixture is homogeneous (inspected by visual inspection). The preconcentrate is filled in a capsule suitable for oral administration. In order to fill the liquid into a two-part capsule or soft capsule, depending on the manufacturer, the viscosity of the formulation must be within a certain range at the fill temperature applicable to the method of the present invention. For both capsules, the maximum fill temperature is approximately 70C. Under normal conditions, the viscosity of the formulation ranges from 50 to 1 000 centipoise (= 0.05" pas) at the temperature selected for the filling method. For the formulation to be filled into a soft capsule, the method temperature must not exceed 3 〇 (the temperature of the 眞 is determined by the manufacturer =). The formulation must be liquid and have a viscosity that is pegable at the filling temperature. To make the formulation a liquid with acceptable viscosity, use some additives, such as CremophorEL®. II. Filling As far as the filling process is concerned, the composition must be in a liquid form at the filling temperature. Therefore, the semi-solid thermosoftening composition is filled at a temperature higher than the liquefaction temperature-----r----------------- Please read the notes on the back and fill out this page) -25 1306030 A7 B7 V. INSTRUCTIONS (23) (Please read the notes on the back and fill out this page). Soft gelatin capsules are manufactured and filled in a single operation and filled at a temperature of up to 4 ° C. However, hard gelatin capsules are filled at temperatures up to 7 ° C. Hard gelatin capsules filled with a composition that is still liquid at storage temperature must be sealed by, for example, gelatin to avoid leakage. The liquid filling method and product requirements for hard gelatin capsules are described, for example, in the first month of 1998, W·j. B〇wtle

Pharmaceutical Technology Europe, March 1999, V. Μ.

Young was published in Pharmaceutical Manufacturing and s〇urcer; and in September/October 1989, E·T c〇〇le was published in Technology Internati〇nai. The use of two-part capsules allows the filling of more than one type of phase into a single capsule, which is desirable for the release of double- or multi-phase drugs (W. j. Bowtle et al., published in Int j). Pham. 141 (1996), pp. 9_16). Several phases of solidified material can be filled in a single step. If desired, the final phase of the i can be liquid. The number of phases is limited only by the size of the capsule and the volume of the single phase. This particular feature also allows control of the release or separation of different drugs formulated in the same capsule. In addition, the capsules can be subjected to further processing, such as intestinal coating. III. Integration with PPI's Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed NS AIDs that release oil or semi-solid NO release in _ containers, adding solid or semi-solid surfactants and solid/oily fats (non- compulsory) . Heating the mixture to a temperature equivalent to the melting point of the excipient, preparing a fluid formulation 'sufficiently mixed until homogeneous (inspected by inspection), and preparing a casing coated with a proton pump inhibitor susceptible to acid Z cough mixture. Filling the suspension-containing PPI_pill pre-concentrate in capsules = This paper scale is applicable to China National Standard (CNS) A4 specification (21〇x -26- 1306030 A7 B7 5. Inventive Note (24), when it is cured, It is suitable for oral administration. In addition, the NSAID of oily or semi-solid NO can be placed in a container, adding a solid surfactant and solid/oily fat (non-mandatory). Heating the mixture is equivalent to The temperature of the melting point of the excipient is prepared to prepare a fluid formulation, which is thoroughly mixed until it is uniform (inspected by visual inspection). The preconcentrate is filled in a capsule suitable for oral administration when it is cured. A protective layer of paraffin is added, Or any other inert heat-softenable matrix suitable for oral administration and curing. The prepared ρρι_ capsule is added to the top of the paraffin. In another alternative method, the NSAID of the oily releaseable NO is placed in a A liquid sensitizing surfactant is added to the granules, the mixture is mixed until uniform (by visual inspection), and the prepared PP pills are filled in capsules suitable for oral administration. IV. Identification of the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives Printing ---------------------------------------------------------------------------------------------------------------------- Once the SGF (without enzyme) is contacted with the experimentally simulated gastric juice, the time required to form the oil-in-water emulsion is formed, and the resulting emulsion is identified. SGF consists of 7 ml of concentrated hydrochloric acid, 2 g of sodium chloride and steamed The water composition 'made a solution with a total volume of 1 liter. The emulsion formation test was carried out in a magnetically stirred test tube (beaker). A test tube containing a small amount of magnet was filled with 12.5 ml of enzyme-free SGF, equivalent to human gastric juice. One tenth of the average volume, and a formula that adds one-tenth the dose of the active compound. If the formula is identified as containing a combination of PPI, the PPL pellet must be tested to protect it from SGF. Completion. If the casing coating of PPI_Pills is affected, this PPI may have a negative effect at pH = 1.2, which can be seen by significant changes in color. _ - 27 - This paper scale applies to the Guanzhong standard ( CNS) A4 specification (210 X 297 public love) ---- 1306030

, the time required for the formation of the ceremony, varies from 30 seconds to 15 minutes, depending on the composition of the formula. If one or more short chain alcohols are added, the time required for emulsion formation will vary from 2-3 seconds to 3-4 minutes. The average particle size of the emulsion formed is measured by laser diffraction (Ld) or photon correlation spectroscopy (PCS). One of the two methods can be used depending on the particle size. DETAILED DESCRIPTION OF THE INVENTION The present invention will now be described in more detail by the following examples, which should not be construed as limiting the invention. The following emulsion preconcentrate was prepared. In the following Examples 1-7, the active compound used in the formulation is a compound of the above formula. Example 1 Content of gram 1 (i) Compound of formula (la) 1 〇〇〇 (ii) Pluronic F127® 1000 obtained by heating to 62 ° C to melt 1 kg of Pluronic F127® (Pol〇xamer 4〇7) to obtain half solid formula. The melt is thoroughly stirred to ensure that no solid particles are present. One kilogram of the compound of formula (la) was added to the flaring Pluronic F 127® and the mixture was allowed to reach a temperature of 62 °C. Mix this liquid formula until it becomes a check mark (by inspection). The resulting liquid formulation is then filled in a hard Mingsheng capsule. The formulation becomes a semi-solid after cooling (in the capsule). Identification 150 mg of the formula into 12.5 ml of SGF (without enzyme) and magnetic -28- This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 public meals) -------- -- (Please read the notes on the back and fill out this page) n I n flu · ^^1 Bi> nn · 11dw Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1306030

Description of the invention (26) . The following results were obtained: Time taken to become the emulsion: 13 minutes: 2-3 micrometers::j system A 20 seconds, force, lower cone and plate viscosity: in the 'measurement system horse c 4 () 4 pc . The flow method is more or less the burdock content of the gram 1 (i) formula da) compound (") Pluronic L121® 1 〇〇〇 A / under the dish 'by taking 1 kg of liquid surfactant 4 〇 1 and 1 A pound of the compound of formula (la) is prepared in a liquid formulation. The liquid formulation is mixed until the wheat is homogeneous (inspected by visual inspection). The resulting liquid formulation is then filled in a hard gelatin capsule. ' Identification ^-----Γ-- -^-------- <Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, print 150 mg of this formula into 12.5 ml of sgF (without enzyme) And magnetic stirring. The following results were obtained: Time taken to become an emulsion: 20 seconds Average particle size: 1 1 micron Example 3 - Content gram 1 (〇1 (1) compound 1000 (Π) Polyglycol BM 45® 1000 (iii) Sodium lauryl sulfate 40 -29- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1306030 V. Description of invention (27) By mixing 1 kg of polyglycol BM 45 ® (Pol〇xamine 11〇7), 4 grams as a total of 2 active agents of sodium sulphate, ^ One kilogram of the compound of formula (iv) is given a formula. Mix the liquid formulation until it becomes uniform (see + test). The resulting liquid formulation is then filled in a hard gelatin capsule." Stirring. Obtain the following results: Time spent in the emulsion : 15 min average particle size: 0.7 μm Example 4 Content coupons. 1 (i) Formula (la) Compound 1000 (ii) Pluronic F127® 500 (iii) Cremophor EL® 500 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed as The semi-solid formulation can be filled in a soft gelatin capsule at a temperature of less than 30-40 ° C (why the specific temperature depends on the manufacturer). This means that the formula must be liquid and at 30-40X: The lower system is pumpable. To obtain a fluid formulation at this temperature, some surfactants are replaced by Cremophor EL®. A melt is prepared as described in Example , except that the same amount of Cremophor EL® is substituted for 0.5. Kg of surfactant. Identification 150 mg of this formula was placed in 12·5 ml of SGF (without enzyme) and magnetically stirred. The following results were obtained: It takes time to emulsion: 9 minutes -30-

This paper size is suitable for the Knockout (CNS) A4 specification (210 X 297^iT installation -------- order -------- (please read the note on the back and fill out this page) 1306030 ^___ . Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 Invention Notes (28) Average Particle Size: 4-5 μm Example 5 Content 1 " Fragrance, 1 (i) Formula (la) Compound 1250 (ii) Pluronic F127® 1500 (iii) Fractionated Coconut Oil 1880 Divides the active ingredient to ensure that the low-dose formulation has good filling accuracy and that the filling volume of the capsule reaches a certain volume to minimize the amount of air present. The portion is filled with coconut oil. By heating to 62-C to melt 1 500 kg? 1111 * 〇 11 丨 (: ^ 127 @ (? 〇 1 (^11 ^ 407) to obtain a half solid formula. Melt to ensure that no solid particles are present. 1.250 kg of the compound of formula (ia) and 1 880 kg of the portioned coconut oil are added to the molten Pluronic F127® and the mixture is allowed to reach a temperature of 62 t. The formula until it becomes uniform (by inspection) ^ then fill the resulting liquid formula In a gelatin capsule. One-tenth of the formulation was placed in 12.5 ml of SGF (without enzyme) and magnetically stirred. The following results were obtained: Time taken to become the emulsion: 10 min Average particle size: 5 μm Example 6 Content "g 1 (1) formula (la) compound 62.5 (ii). PluronicF127® 375 L_____-31- This paper scale off + _ ¥ standard (CNS) A4 specification (10) χ tear ip------ ---- ------Install-----:----Book--------. (Please read the notes on the back and fill out this page) 1306030 A7 B7 V. Invention Description (29) (iii) Fractionated coconut oil 312.5 (Please read the note on the back and fill out this page) Prepare the formulation as described in Example 5 above. Identify the work identified as in Example 5 above. Obtain the following results: Time spent: 10 minutes average particle size: 36 microns Example 7 Content "gram 1 (i) formula (la) compound 62.5 (ii) Pluronic F127® 375 (iii) fractionated castor oil 312.5 prepared as described in Example 5 above This formulation. The work identified as in Example 5 above was identified. The following results were obtained: Fee time: 10 minute average particle size: 81 m Example 8 The active compound of the formula (LB) used in the present invention Example 8 formulations. Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Content "g 1 (i) Formula (lb) Compound 75 (ii) Polyglycol BM45® 75 A formulation was prepared in the same manner as in the previous examples. Time taken to identify the emulsion: 1.5 minutes _-32-_ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau Consumer Cooperative Printed 1306030 V. Invention Description (3 〇) Average particle size: The above formula (IC) active compound (1) Formula (Ic) Compound (ii) Polyglycol BM45® was prepared in the same manner as in the previous examples - Identification of time taken to become an emulsion: Average particle size: Example 1 0 The above-mentioned active compound of the formula (10) was used in the present invention Example 1 〇 Formulation ± ΛΛ 1 Δ (i) Formula (Id) Compound 75 (ii) Polyglycol BM45® 5 A formulation was prepared in the same manner as in the previous examples. The time taken to become the emulsion was identified: 〇.5 minutes average particle size: 2 μm Example 11 The above-mentioned active compound of the formula (Ie) was used in the formulation of the present invention. The content of the formula 1 (i) the compound of the formula (Ie) 75 (ii) Polyglycol BM45® 75 This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 5 micron

33- 1306030 A7 V. INSTRUCTIONS (B7 31 The time taken for the identification of the first one by the same method as the previous example: a Average particle size: 1 minute Example 12 4 μm The economical formula of the above formula (If) The Ministry of Intellectual Property's employee consumption cooperative printed the same method used in the formulation of Example 12 of the present invention in the same manner as in the above-mentioned example of the formula 1 75. The time taken to convert the emulsion into the emulsion: Average particle size: Example 13 The above formula (Ig) active compound is used in the present invention in Example 1 where the content is ίgΊ (1) Formula Ug) Compound 75 (Η) Polyglycol BM45® 5 The formulation is prepared in the same manner as in the previous examples. Identification - Time average particle size taken for (If compound (ii) polyglycol BM45 to become an emulsion: Example 14 1 minute 2 micron 3 minutes 1 micron The above formula (la) and (Ik) active compound were used Inventive Example 14 Formula ----------- Pack-----„----订-------- <Please read the notes on the back and fill in this page) - 34- The paper size is suitable for the financial standard (CNS) A4 specifications (10) χ 297 public love 1306030

V. Description of the invention (32 content: [1. 2,250,250] by formulating a compound of formula (Ih) in a compound of formula (Ia), and then Pluronic L121® (p〇i〇xamer 4〇1) The mixture was added to the mixture until it became homogeneous (inspected by visual inspection). The formulation was placed in 20 ml of SGF (without enzyme) under magnetic stirring. The time taken to measure the emulsion was obtained. The following results were obtained: Time taken to become an emulsion: 5-10 seconds Example 1 5 The above formula (Ia) and (π) active compound are used in the formulation of the inventive example 1 5 (i) the compound of the formula (la) (ii) the formula (Ik) Compound (iii) Pluronic L121 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed (I) Compound (la) (II) Compound of formula (Ii) (Pluronic L121®) Prepared as Example 14 - Formulation As identified in Example 14 above The time it takes to become an emulsion: Content [g 1 250 8 250 3 minutes. - . C Pack-----r---订---------------- - (Please read the notes on the back and fill out this page)

-35- (210 X 297 mm) l3〇6〇3〇

V. Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printing Instructions (33) X Example 1 6 Contents gram 1 (i) Formula (la) Compound 750 (ii) Pluronic F 127® 45 〇 (iii) Omeprazole 20 by heating A half solid formulation was obtained by melting 450 grams of Pluronic F127® (Poloxamer 407) to 62 °C. The melt is thoroughly stirred to ensure that no solid particles are present. Adding 750 g of the above compound (la) to the melted

Pluronic F 127® and let the mixture reach a temperature of 62 。. 20 g of the omeprazole Mg salt prepared as described in WO 96/01623 'Example 2 was added as an enteric layer coated pellet of Omeprazole. Mix this liquid formula until it becomes uniform (inspected visually) and then fill it in a hard gelatin capsule. The formulation becomes a semi-solid after cooling (in the capsule). Identification 120 mg of this formulation was placed at 37 ° C in 12.5 ml of SGF (without enzyme) and magnetically stirred. SEDDS will form an emulsion upon contact with SGF. The PPI-pill does not have any change in the environment of SEDDS and pH = 1.2, as can be seen from any change in color. The time it takes to become an emulsion is 丨2/8 0 Example 1 7 (i) Formula (la) Compound 750 (ii) Pluronic L121® 450 (iii) Omeprazole 20 -36- This paper scale applies to China National Standard (CNS) A4 Specifications (210 X 297 mm) Pack *----r---book--------. (Please read the notes on the back and fill out this page) 13〇6〇3〇

Content [g 1 3 0.843 0.282 0.375 Ministry of Economic Affairs Intellectual Property Bureau Consumer Cooperative Printed 5, Invention Description (34) A胍 borrowed; Kunhe 450g liquid surfactant p〇i〇xarner 401 and 750g above (la The compound is prepared in a liquid form. Omeprazole in the form of a % coat coated pill comprising the 〇mepraz〇le Mg salt prepared as described in Example 2 of WO 96/01623' was added. Mix this liquid formulation until it becomes uniform (inspected visually) and fill it in a hard gelatin capsule. Identification 120 mg of this formulation was placed under 37X: 12.5 ml of SGF (without enzyme) and magnetically stirred. SEDDS will form an emulsion upon contact with SGF, and the PPI-pill does not have any change in the environment of SEDDS and pH = h2, as can be seen from any change in color. The time it takes to become an emulsion is 0.5 minutes. Example 1 8 (i) Compound of formula (la) (ii) Pluronic L127® (iii) sorbitan monolaurate (iv) Glycerol is heated to 62 ° C to melt 0_843 grams of Pluronic F127® (p〇i 〇Xamer 407), 0.2 82 g of sorbitan monolaurate and 0.375 g of glycerol obtained a half solid formulation. The melt is thoroughly stirred to ensure that no solid particles are present. 3 grams of the compound of formula (la) is added to the mixture. Let the mixture reach a temperature of 62 °C. Mix this liquid formulation until it becomes uniform (depending on inspection). Cool the resulting liquid formula to 30 °C, then fill it in soft-mounted ------------------------- (Please read the note on the back and fill out this page) - 37- 1306030 Printing and mixing of employees' consumption cooperatives of the Intellectual Property Office of the Ministry of Economic Affairs. The following results were obtained: Time taken to become an emulsion: 2.5-3.5 minutes Example 1 Gold amount 1 (i) Compound (la) 3 (ii) Pluronic L127® 0.843 (ill) sorbitan monolaurate 0.282 ( Iv) Polyethylene glycol 〇.375 A7 _________B7 V. Description of invention (35) In capsules. The formulation becomes a semi-solid after cooling (in the capsule). Identification & 2 mg of this formula was placed in 12.5 ml of SGF (without enzyme) and heated to 62 by magnetic. (: a half solid formulation was obtained by melting 0.843 g of Pluronic F127® (P〇l〇xamer 4〇7)' 〇 282 g of sorbitan monolaurate and 375 375 g of polyethylene glycol. Melt to ensure that no solid particles are present. Add 3 grams of the compound of formula (ia) to the mixture. Let the mixture reach a temperature of 62 ° C. Mix the liquid formulation until it becomes homogeneous (inspected by inspection). At 30 ° C, it is then filled in a soft gelatin capsule. The formula is still a liquid after cooling (in the capsule). Identification 1123⁄4 grams of this formula is placed in 12.53⁄4 liters of SGF (without enzyme) and For magnetic stirring, the following results were obtained: Time taken to become an emulsion: Example 20 content in 20 seconds "g 1 ______ -38- This paper scale applies to China National Standard (CNS) A4 specification (2) 〇x 297 public) "II Pack —--r---订-------- <Please read the notes on the back and fill out this page.) 31306030 A7 V. Description of invention (36) (1) Compound of formula (la) 0.506 0.169 0.225 (ii) Pluronic Ll〇i® (please read the notes on the back first) Complete this page (iv) Preparation of ethanol (iii) sorbitan monolaurate) - liquid formulation. Mix 〇5〇6g of piur〇nic u〇i@ (4) (4) 331), 0. 169 grams of sorbitan monolaurate and 0.225 grams of ethanol until they become homogenized (by visual inspection). 3 grams of the compound of formula (10) was added to the mixture at room temperature. The resulting liquid formulation was filled in a soft gelatin capsule. Identification 97 mg of the commercial ingredient was placed in 12.5 ml of coffee (without enzyme) and magnetically stirred. The following results were obtained: Time taken to become the emulsion: Within 20 seconds Formulated in vivo in mini-pigs The nailed mini-pigs were orally administered and the bioavailability studies of the formulations according to the invention were carried out. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the employee consumption cooperative. In this study, six male G0ttingen SpF mini pigs were used. At the beginning of the adaptation period, the animal was four months old and weighed between 7 7 and 1 kg. The animals were nailed for up to 12 hours prior to treatment and until the blood samples were ingested after 4 hours of treatment. Compressed hay feed is also provided daily. The animal body is supplied with household quality drinking water twice a day. The pharmaceutical composition according to the present invention, which is filled in a suitable unit dose form, is administered to each animal. The dose is about 5 micromoles per kilogram of body weight administered. Give 10 ml of tap water to help the capsule or equivalent unit dose of the swallow. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1306030

V. Description of invention (37) Every day, it is often the case that δ has recorded that the animal will take blood from the air; the sputum records all the morbidity or health status of the drink, and, “day 7 visible signs. Any deviation from the cause of the accident (initial The duration of the onset of the disease and its severity are also included. The daily health check also includes the observation of the consistency of the stool. The body is weighed at the initial arrival and on the first day of each treatment. Blood samples (5 ml) were placed in heparin-containing sputum container tubes. They were taken before treatment (〇 minutes), at 5, 30 and 45 minutes after treatment, and after 1, 1.5, 2, 4, 7 and 24 hours after treatment. Blood sample - 丨 - 丨 · - rill rill rill rill rill rill rill rill rill rill rill rill rill rill rill rill rill rill rill rill rill rill rill 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 -40 -40 -40 -40 -40 -40 -40 -40 Applicable to China National Standard (CNS) A4 specification (210 X 297 mm)

Claims (2)

Patent application (00104121) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 dongdong) 1306030 A8 B8 C8 D8 VI. Application for patent garden CH. QK CH: :H-CH CH- (ii) one or more surfactants; (iii) an oil or semi-solid moon as the case may be. Once the composition is in contact with an aqueous medium (such as an oil-in-water emulsion). The pharmaceutical composition of the first item, which is a variety of short-chain alcohols. Intestinal fluid) may include one or three in the original step when contacting. The pharmaceutical composition according to claim 1 or 2 of the patent application is free from the spacer X of the NSAID in which NO can be released from the linear, branched or cyclic form. Alkyl-(CH2)-n, wherein n is an integer from 2 to 10; -(CH2)m-〇-(cH2)p-, wherein m and p are integers from 2 to 10; and -CH2- pC6H4-CH2-. 4. The pharmaceutical composition according to claim 1 or 2 of the patent application, wherein the < -2 This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 8 8 8 8 ABCD 1306030 Patent application scope The NS AID for NO release is selected from any of the following compounds CH ·» (la) (lb) (Id) ΟΝΟ, (lc) (le) 3- The paper size is based on the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1306030 8 8 8 8 A BCD This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1306030 C8 D8 This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) AB c D 1306030 VI. Patent application scope 5. The pharmaceutical composition according to claim 1 or 2 of the patent application further contains susceptible to acid. A separate casing coating unit of a proton pump inhibitor or a pharmaceutically acceptable base salt thereof. 6. The pharmaceutical composition according to claim 5, wherein the proton pump inhibitor susceptible to acid is selected from the group consisting of a compound of formula I or a pharmaceutically acceptable base salt thereof, or a single mirror image isomer thereof Or the base salt of the single mirror image isomer 0 II τ HetpX-S-Het, I wherein HetA or 5 R Het2 is or Or Μ Ν- -6 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1306030 A8 B8 C8 D8 VI. Patent application scope 12 or -CH——I ^10 wherein N in the benzimidazole moiety represents one of the carbon atoms substituted by R6_r9, optionally substituted by a nitrogen atom without any substituent; Rz and R3 are the same or different' and Is selected from the group consisting of hydrogen, alkyl, alkoxy', as the case may be, by gas, sulphur, sulphur, alkoxy, alkoxy, acetophenone, morpholinyl, phenyl, phenyl and phenylalkoxide. Substituted; R·4 and R_5 are the same or different and are selected from hydrogen, alkyl and aralkyl; RV is hydrogen, halogen 'trifluoromethyl' alkyl and alkoxy; RrR9 is the same or different And is selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, halogen-oxyl, alkylcarbonyl 'oxycarbonylcarbonyl, oxazolyl, sulphonate' or an adjacent R^-Rs» group a ring structure which may be further substituted; Rio is hydrogen or forms a chain of extension with R3, and Rn and Ri2 are the same or different and are selected from hydrogen, halogen or alkyl, alkyl 'alkoxy Part of it may be a branched or straight Cl-C9-chain or a cycloalkyl group such as a cycloalkyl-alkyl group. 7. The pharmaceutical composition according to claim 6 wherein the proton pump inhibitor is selected from any of the following compounds - 7 - The paper size applies to the Chinese National Standard (CNS) A4 specification (210) X 297 mm) 1306030 VI. Patent application scope 8 8 8 8 AB c D och3 CH 3 Η c Omeprazole N- -O OII s Lansoprazole OCH, OCH, 〇'Ν' CH, 〇II N OCHF, S, N Pantoprazole H -8 This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1306030 Patent application scope 8 8 8 8 ABCD Pariprazole 〇II Leminoprazole SIS: Η CH CH This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1306030 as B8 C8 ---- VI. Patent application scope 8. The pharmaceutical composition according to claim 7 wherein the proton pump inhibitor susceptible to acid is selected from the salt salts of omeprazole, omeprazole base salts '(S)-omeprazole and (s)-omeprazole. The pharmaceutical composition according to claim 8 wherein the alkali salt of the omeprazole or (S)-omeprazole is a magnesium salt. 10. The pharmaceutical composition according to claim 5, wherein the NS AID capable of releasing NO is a compound of the formula la, and the proton-dependent inhibitor of the acid is selected from the group consisting of omeprazole, an alkali salt of omeprazole, (S Base salts of -omeprazole and (S)-omeprazole. -10- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ' · 1306030 A8 B8 C8 ____D8_____ VI. Patent application scope - According to the pharmaceutical composition of claim 1 or 2, The amount of NSAID that can release NO is 50-1500 mg per unit dose. 12. The pharmaceutical composition according to the scope of the patent application, wherein the content of the NSAID of the releaseable meno is 125-500 mg per unit dose. U. The pharmaceutical composition according to claim 1 or 2, wherein the surfactant is a block copolymer. 14. The pharmaceutical composition according to claim 1 or 2, wherein the surfactant is a nonionic surfactant. The pharmaceutical composition according to claim 16, wherein the nonionic surfactant is p〇l〇xanier. The pharmaceutical composition according to claim 4, wherein the interfacial activator is selected from the group consisting of Poloxamer 407; Poloxamer 401; Poloxamer 237, Poloxamer 338; Poloxamer 331; Poloxamer 231; Poloxamine 908; P〇l〇xamine i3〇7; P〇1〇xaminell〇7; and polyoxyethylene polyoxybutylene block copolymer. Π. According to the scope of the patent application! Or a pharmaceutical composition of 2, wherein the total amount of the surfactant is from 12.5 to 6000 mg. 18_ The pharmaceutical composition according to claim 17, wherein the total amount of the surfactant is from 100 to 500 mg. 19. The pharmaceutical composition according to claim 1 or 2, wherein the NSAID capable of releasing NO: the proportion of the surfactant is in the range of 丨:〇.丨_丨:丨〇. 2〇 The pharmaceutical composition according to claim 19, wherein the NSAID capable of releasing n〇: the proportion of the surfactant is: 3. 21. According to the scope of the patent application! Or 2 medical compositions, which have -11 - I paper scale applicable to Chinese National Standard & NS) A4 specification (210X297 public) '~" - I3〇6〇3〇A8 P^_ B8 ^ ----_____ C8 Acupoints, ^ϊϊϊϋϋ ~' ~ Oil e 22 i • The pharmaceutical composition according to claim 21 of the patent application, wherein the oil is vegetable oil. The pharmaceutical composition of claim 22, wherein the vegetable oil is selected from the group consisting of coconut oil, corn oil, soybean oil, rapeseed oil, safflower oil and castor oil. 24. The pharmaceutical composition according to claim 21, wherein the oil is an animal oil. A pharmaceutical composition according to claim 24, wherein the animal oil is fish oil or one or more mono-, di- or triglycerides. 26. The pharmaceutical composition according to claim 1 or 2, wherein a semi-solid fat is used as a filler. 27. The pharmaceutical composition according to claim 26, wherein the semi-solid fat is selected from the group consisting of mono-, di- and triglycerides. 28. The pharmaceutical composition according to claim 27, wherein the mono-, di- or diglyceride is selected from the group consisting of palm stearic acid glycerin vinegar, or glycerol mono- and di-acetate , mono- and di-esters of polyethylene glycol or free polyethylene glycol. 29. The pharmaceutical composition according to claim 2, wherein the short chain alcohol is selected from the group consisting of ethanol, propylene glycol or glycerin. 3〇·According to the scope of patent application! Or a pharmaceutical composition of two, further comprising a co-surfactant. 3L - a unit dosage form filled with a medical music composition according to the scope of the patent application. -12· 1306030•利范园^ 8 8 8^ ABCD 32·According to the application of the 5th patent holder cage 3 1 Gongyue yue j target morning siblings 31 items, which are selected from drinking ampoules, dose 塾, can sound > sac, one of them. J and 莳 soft-style music pills, and not easy to chew 33. According to the scope of the patent application scope of the unit of the general public, and not easy to mouth broken swords, the dosage form is in the form of a capsule 34. According to the scope of patent application 33 type gelatin capsules. The early dosage form 'where the capsule is a hard 35 · root shot patent model' is called a gelatin capsule. The soap position is 'the type of capsule' is 敕36. According to the scope of the patent application, the pain is treated. S medical composition It is used to treat the eyelashes according to the scope of the patent application. The medical composition of the S member is used to treat the paper scale stone -13 - 10 x 297 mm)