CA2145763A1 - Pharmaceutical compositions containing nonionic surfactants - Google Patents
Pharmaceutical compositions containing nonionic surfactantsInfo
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- CA2145763A1 CA2145763A1 CA002145763A CA2145763A CA2145763A1 CA 2145763 A1 CA2145763 A1 CA 2145763A1 CA 002145763 A CA002145763 A CA 002145763A CA 2145763 A CA2145763 A CA 2145763A CA 2145763 A1 CA2145763 A1 CA 2145763A1
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- nonionic surfactant
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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Abstract
Pharmaceutical compositions comprise an enzymatically labile pharmaceutically active agent which is permeable through the intestinal wall or requires an intestinal permeability enhancer to permeate the intestinal wall, and at least one nonionic sur-factant which is capable of protecting said active agent against deactivation by enzymes. A method for the inhibition of the de-gradation of an enzymatically labile pharmaceutically active agent by gastrointestinal enzymes comprises combining said agent with a nonionic surfactant.
Description
W O 94/07472 2 1 4 5 7 6 3 PC~r/US93/08107 Backqround of the Invention This invention relates to pharmaceutical compositions containing nonionic surfactants, to methods for the inhibition of the degradation of certain pharmaceutically active agents by combining them with nonionic surfactants, and to methods of co-10 administering said active agents and said nonionic surfactants.
The co-administration of a pharmaceutically active agent with a surfactant is mentioned in Swenson and Curatolo, Advanced Drug Delivery Reviews, 8, 39-92 (1992).
The surfactant is described as enhancing the permeability of a drug through the intestinal wall.
United States Patent No. 4,579,730 suggests that the ionic bile salt sodium cholate, which is a surfactant, functions as a protease inhibitor in the small intestines so promoting absorption of insulin. The general use of surfactants as protease inhibitors in the gastrointestinal tract is not suggested.
The use of non-surfactant protease inhibitors as protectants against gastrointestinal proteases has been described in Lee, J. Controlled Release, 13(1990)213-223, Ziv et al, Biochem. Pharmacol., 36(1987)1035-1 039, and U.S. Patent 4,579,730. Hayakawa et al, Life Sciences 45,167-174(1989), reports that the bile salt sodium glycocholate and the nonionic surfactant polyoxyethylene-9-lauryl ether either inhibit or stimulate degradation of insulin by nasal homogenates, depending on the concentration of the surfactants. European Patent Publication No. 33~ discloses that the protease activity of vaginal washings is decreased in the presence of the anionic surfactant sodium dodecyl sulfate and also discloses a method of vaginalcoadministration of an ionic or nonionic surfactant with a biologically active polypeptide to inhibit vaginal protease at the site of adl"ini~ lion.
In accordance with the invention, pharmaceutical compositions for oral administration are provided comprising an enzymatically labile pharmaceutically active agent which is permeable through the intestinal wall and at least one nonionic surfactant which is capable of protecting said active agent against deactivation by enzymes.
In one embodiment of the invention, the active agent tS a peptide having a molecular weight of less than about 3,000. Examples of suitable nonionic surfactants are ethoxylated alcohols, ethoxylated fatty acids, sorbitan derivatives and ethoxylated 2 ~ 1 ~ 5 7 ~ 3 - PCI/US93/08107 alkyl phenols, specifically ethoxylated lauric acid, polyoxyethylene(40)stearate, polyoxyethylene(20)sorbitan monooleate, polyoxyethylene(23)1auryl ether, nonylphenoxypoly(ethyleneoxy)ethanol-30, nonylphenyoxypoly(ethyleneoxy)ethanol-50, or a mixture of glylceryl and polyethylene glycol-1500 esters of paim kernel oil.
In another embodiment of the invention, an oil is included in the composition.
i-xamples of suitable oils are monoglycerides, e.g., mono-octanoin or monodecanoin, digiycerides, e.g., glyceryl-1,2-dioctanoate, and triglycerides, e.g., vegetable oil or caprylic/capric triglyceride.
The invention also provides a pharmaceuticai composition for orai administrationcomprising (1 ) an enzymatically labile pharmaceutically active agent which is permeable through the intestinal wall only in the presence of an intestinal permeability enhancer, (2) at least one nonionic surfactant which is capable of protecting said active agent against deactivation by proteolytic enzymes and which is not an intestinal permeability enhancer, and (3) an intestinal permeability enhancer which is other than said nonionic surfactant. In one embodiment, this composition comprises a nonionic surfactant having an HLB of about 14 to about 20.
The invention also provides a pharmaceuticai composition for orai acJI~ ,i"isl~ alion comprising (1) an enzymatically labile pharmaceutically active agent which exerts its therapeutic activity locally in the stomach or intestine, and (2) at least one nonionic sur~actant which is capable of protecting said active agent against deactivation by enzymes.
The invention further provides a method for inhibition of the enzymatic degradation of an enzymatically labile pharmaceutically active agent which is permeable through the intestinal wall by combining said active agent with a nonionic surfactant which is capable of protecting said active agent against deactivation by enzymes.
The invention also provides a method for the oral administration of an enzymatically labile pharmaceutically active agent which is permeable through the intestinal wall to a host which comprises co-administering to said host said active agent and at least one nonionic surfactant capable of protecting said active agent against deactivation by enzymes.
The invention yet further provides for a method for the oral administration of an enzymatically labile pharmaceutically active agent which is permeable through the intestinal wall only in the presence of an intestinal permeability enhancer by co-WO 94/07472 2 1 4 5 7 6 3 PCI~/US93/08107 administering to said host said active agent, at least one nonionic surfactant which is c~p~hle of protecting said active agent against deactivation by enzymes and which is not an intestinal permeability enhancer, and an intestinal permeability enhancer which is other than said nonionic surfactant.
The enzymatically labile pharmaceutically active agents of the invention containenzymatically labile bonds, such as ester, amide and/or peptide bonds, and are inactivated by digestive enzymes in the gastrointestinal tract. Examples of suchdigestive enzymes are pepsin, trypsin, chymotrypsin, elastin, aminopeptidase, carboxypeptidase, lipase and intestinal glycosid~es and esterases.
Examples of enzymatically labile pharmaceutically active agents (the active agents) are calcitonin, prolactin, adrenocorticotropin, thyrotropin, growth hormone, gonadotropic hormone, oxytocin, vasopressin, gastrin, tetragastrin, pentagastrin, glucagon, insulin, secretin, substance P, gonadotropin, leutinizing hormone releasing hormone, leuprolide, enkephalin, follicle stimulating hormone, cholecystokinin, thymopentin, endothelin, neurotensin, i"te"eron, interleukins, insulinotropin, and therapeutic antibodies; and analogues of the above agents, which possess D-aminoacids, blocked amino or carboxyl end groups e.g., nafarelin acetate and YdAGFdL (an enlaphalin analogue), and non-natural amino acids such as S-methyl cysteine and statine. Also included are purified extracts of natural origin and their chemical modifications, as well as products obtained by tissue culture and products obtained by cultivating microorganisms or cells rendered productive by genetic engineering techniques. Also included are synthetic peptides and derivatized synthetic peptides such as terlakiren (isopropyl-N-[N-(4-morpholine-carbonyl)-L-phenylalanine-S-methyl-cysteine]-2(R)-hydroxy-3(S)-amino-4-cyclohexylbutanoate) disclosed in U.S. Patent 4,814,342, Example 4 thereof, which is incorporated herein by reference. Furtherincluded are prodrugs of the active agents, i.e., derivatives of the active agent which convert to the active agent in vivo.
The active agents further include prodrugs of a pharmaceutically active compound which itself may not contain an enzymatically labile bond. Such prodrugs are themselves enzymatically labile by connection of the prodrug group to the pharmaceutically active compound through an enzymatically labile bond such as anester or amide bond.
WO 94/07472 . ~ 1 4 5 7 6 3 ; PCI`/US93/08107 According to the invention, when the active agent is permeable through the intestinal wall, it is co-administered with at least one nonionic surfactant which is capable of protecting the active agent against deactivation by enzymes. The nonionic surfactant is used in an amount which is effective in protecting the active agent against deactivation by enzymes.
In general, an active agent or prodrug is considered permeable through the intestinal wall if it can permeate the intestinal wall without the aid of a permeability enhancer. The intestinal permeability of the enzymatically labile active agent or prodrug is determined by perfusion of a solution of the active agent or prodrug through a segment of the intestine of an anesthetized rat. This test must be carried out in the absence of digestive enzymes to reduce enzymatic degradation of the tested active agent or prodrug. The intestinal segment therefore must be properly washed before the test or the test must be in the presence of inhibitors of digestive enzymes, such as Bowman-Birk trypsin/chymotrypsin inhibitor.
For the purposes of the invention, the enzymatically labile active agent or prodrug is considered permeable through the intestinal wall when it has a P pp greater than about 3.5 X 10 6 cm/sec. The P pp of a compound may be determined from the following equation:
KA = A X P~l~r (1 ) V' wherein KA jS the absorption rate constant of the compound, A jS the surface area of the intestinal segment, and V is the volume of the intestinal segment. When the intestinal segment is cylindrical and the intestinal radius is about 0.2 cm, as in the rat, A/V is about 10 cm~'.
The absorption rate constant KA for a compound is calculated in the rat intestinal permeability test from the following equation:
KA = Q(1-CJC;) (2) V
30 wherein Cj is the concentration of the compound at the start of the test, C0 is the concentration of the compound in the perfusate after passage through a 22 cm intestinal segment, Q jS the flow rate and V is the volume of the intestinal segment, as mentioned above.
WO 94/07472 ~ 1 4 5 7 6 3 PCI/US93/08107 Terlakiren is an example of an enzymatically labile drug which has good intestinal permeability, and does not require a permeability enhancer to achievesignificant oral absorption. Terlakiren has a KA Of 0.02 min-1, a P pp of 3.3 x 1 0 5 cm/sec, , and an aqueous solubility of 0.08 mg/ml.
Friedman and Amidon, Pharmaceutical Research, 8,93-96 (1990), as~esses the permeability of the pentapeptides Leu-enkephalin and Leu-D(Ala)2-enkephalin using the rat intestinal perfusion model. Analysis of the data in the reference using the above equations (1 ) and (2) results in a P~pp value of 1.3 X 10-3 cm/sec for both enkephalins.
These compounds are thus permeable under the definition of permeability of the invention. These compounds are also enzymatically labile. An example of an enzymatically labile compound which is impermeable under the above definition ofpermeability according to the invention is insulin having a P pp of 4.97 X 10-7 cm/sec.
In general, the coadministration of nonionic surfactants with an enzymatically labile pharmaceutically active agent or prodrug will protect the agent or prodrug from enzymatic hydrolysis when the surfactant and the agent or prodrug are coadministered orally, rectally, nasally, or vaginally.
Examples of permeable active agents are peptides with a molecl l15~r weight of less than about 3,000 and more than about 200, which are passively absorbed by the intestinal wall, and dipeptides having a molecular weight of about 200, which are actively transported. As the polarity of the peptide decreases, its permeabilityincreases. However, above a molecular weight of about 2000 to about 3000, permeation will not generally occur without the aid of a permeability enhancer. Specific examples of peptides having a molecular weight of less than about 2,000 and therefore being permeable, are oxytocin, vasopressin, leutinizing hormone releasing hormone, leuprolide, enkephalin, thymopentin, octreotide, thyrotropin releasing hormone, CCK-8, bradykinin, angiotensin 1, somatostatin, desmopressin, substance P, and gonadotropin releasing hormone. Specific examples of peptides having a molecular weight of about 3,000, and therefore being slowly permeable, are calcitonin, glucagon, secretin,endorphin, and insulinotropin.
Examples of active agents which exert their therapeutic activity locally in the stomach or small intestine are anti-ulcer medications such as ~ucralfate, cholesterol lowering agents such as cholestyramine, hormones such as gastrin and cholecystokinin, antibiotics and other therapeutic agents.
WO 94t07472 ~ 1 4 5 7;6~`3 PCr/US93/08107 I . ~,. . . ..
Those surfactants which are capable of protecting the active agent against deactivation by enzymes (protective surfactants) may be identified by an in vitro enzyme inhibition assay as described in Examples 1, 2 and 11.
Examples of more preferred protective nonionic su~factants are as follows:
Chemical Descli~lion ¦ Example ¦ HLB
Sucrose Faffy Acid Ester Sucrose monolaurate Ryoto Sugar Ester LWA 1540 15.0 Sucrose monooleate Ryoto Sugar Ester OWA 1570 15.0 Sucrose monopalmitate Ryoto Sugar Ester P157015.0 Sucrose monostearate Ryoto Sugar Ester S157015.0 Sorbitan Derivatives POE (20) sorbitan monooleate Tween 80 15.0 POE (20) sorbitan monostearate Tween 60 14.9 POE (20) sorbitan monolaurate Tween 20 16.7 15 Ethoxylated Faffy Acids POE (40) stearate Myrj-52 16.9 glyceryl and PEG 1500 esters of Gelucire 44/14 14.0 fatty acids from palm kernel oil Ethoxylated lauric acid Acconon 1000 ML 16.5 20 Ethoxylated Alcohols POE (23) lauryl ether ¦ Brij-35 ¦ 16.9 Ethoxylated Alkyl Phenols Nonylphenoxypoly(ethyleneoxy)- Igepal C0-970 18.3 ethanol Igepal CO-710 14.0 25 Miscellaneous Saturated polyglycolyzed glyceride ¦ Labrasol ¦ 14 Examples of preferred nonionic surfactants are as follows:
WO 94/07472 ~ i 7 ~ ~ PCr/US93/08107 Chemical Descri~lion Example HLB
Apricot kernel oil PEG-6 complex Labrafil M1944CS 3.0 Polyoxyl 35 castor oil Cremophor EL 12-14 PEG-6 octanoic/decanoic Softigen 767 17 5 glycerides Polyoxyethylated vegetable oil Emulphor EL-620 12 Sorbitan mono-oleate Span 80 4.3 Poloxamers Pluronics 14-20 Polyoxyethylene glycerol TagatTO 11.3 10 trioleate Sorbitan mono-laurate Span 20 8.6 Acetoglycerides Myvacets 3.8-4.0 Decaglycerol mono/dioleate Caprol PGE860 11 Polyoxyethylene(4)1auryl ether Brij 30 9 5 POE 9 mono-oleate Pegosperse 400 MO 11 POE (20) sorbitan trioleate Tween 85 11 POE (4) sorbitan monolaurate Tween 21 13.3 Mono/diglycerides of Imwitor-742; Capmul-MCM 5.5-6 octanoic/decanoic acids Glycerol Mono-oleate Capmul-GMO 3.4 Mono-octanoin Imwitor-308 6 An oil may be coadministered with the active agent and the protective nonionic surfactant. In the context of the invention, an oil is a liquid which is il,lrlliscible with 25 water. The oil may aid in solubilization of the active agent where the active agent is non-polar. In some cases, the oil may also be a protective surfactant, for instance Capmul-MCM (monooctanoin). Other suitable oils include triglycerides, diglycerides, and monoglycerides. The monoglycerides, e.g., mono-olein, and mono-octanoin (Capmul MCM; Imwitor-308), are unusual in that they are polar oils, compared to di-30 and tri-glycerides, and, can also be surfactants or emulsifiers. The monoglycerides may serve as emulsifiers when mixed with non-polar oils such as triglyceride vegetable oils or medium chain C4-C12 triglycerides such as Miglyol-812. When the monoglyceride WO 94/07472 ~ ~L 4 ~ PCr/US93/08107 is the protective surfactant of the formulation, the monoglyceride serves as the water-immiscible oil phase. In that case, an additional surfactanVemulsifier may be included to emulsify the monoglyceride oil in the aqueous use environment. When an additional surfactanVemulsifier is not present, the monoglyceride can serve both as oil phase and 5 surfactanVemulsifier. For example, when mono-octanoin (Capmul-MCM) is released in an aqueous use environment, it serves both as an oil and a surfactanvemulsifler.Suit~hle combinations of surfactant and oil include Tween-80 with Miglyol-812 or Capmul-MCM, and Labrafil-M-1944CS with Miglyol-812. Mixtures of more than twosurfactants and oils are possible. For example, Tween-80 and Capmul-MCM may be 10 combined with Miglyol-812.
Suitable oils for use in this invention are:
Example Chemical Description Miglyol 812 Octanoic/Decanoictriglyceride Soybean oil Vegetable oil Sesame oil Vegetable oil Olive oil Vegetable oil Oleic acid Fatty acid Imwitor-308 Mono-octanoin Imwitor 742; Capmul-MCM Mono/di-glyceride of octanoic and decanoic acids Lipiodol lodinated vegetable oil Capmul-GMO Glycerol mono-oleate According to the invention, an active agent, which is permeable through the intestinal wall only in the presence of an intestinal permeability enhancer (non-25 permeable active agent) is co-administered with at least one protective nonionic surfactant which is not a permeability enhancer (non-enhancer protective surfactant), and a permeability enhancer which is not the protective nonionic surfactant.
In general, non-permeable active agents do not disappear from the perfusion fluid after about one hour in the above described permeability test. Examples of such 30 active agents are peptides of a molecular weight of more than about 3,000, e.g., prolactin, growth hormone, insulin, gonadotropin, follicle stimulating hormone, interferons, interleukins and therapeutic antibodies.
The ability of a nonionic surfactant to enhance the permeability of a non-permeable active agent may be determined by the following test. A segment of theintestine of an anesthetized rat is externalized, and a solution of the poorly absorbed drug phenol red and the nonionic surfactant to be tested is pumped through the 5 intestinal segment for one hour. At the end of the one hour perfusion, systemic blood is collected and the drug concentration therein is measured, e.g., by high performance liquid chromatography. This test was applied to a series of nonionic nonylphenoxypoly-oxyethylene (NP-POE) surfactants having from 9 to 100 POE units. These surfactants have the non-polar NP segment and the polar POE segment. The more oxyethylene 10 (OE) units, the more polar the surfactant. It was found that the less polar surfactants having 9 to 20 OE units are permeability enhancers, whereas the more polar surfactants having 30 to 100 OE units are not. This is illustrated in Table A, which presents plasma phenol red levels at the end of a one hour rat intestinal perfusion with phenol red in the presence of 1% (gm/100 ml) NP-POE-9, -10.5,-20,-30,-50,-100.
Table A
PLASMA PHENOL RED
NP-POE ADDED HLBCONCENTRATION (MCG/ML) NONE - 0.35 NP-POE-9 13.4 22.49 NP-POE-10.5 14.0 31.06 NP-POE-20 16.3 25.47 NP-POE-30 17.4 0.24 NP-POE-50 18.3 0.15 NP-POE-100 19.1 0.42 One method of measuring the polarity of nonionic surfactants is by determining the hydrophile-lipophile balance (HLB), Griffin, J. Soc. Cosmet. Chem., 5, 249-256 (1954). For NP-POE's, those surfactants having an HLB of less than 17 are permeability 30 enhancers and those having an HLB of more than 17 are not. Similarly, for mixtures of NP-POE's of different POE lengths, the HLB of 17 or less is essential for permeability enhancement.
W0 94/07472 ~ 3: i ~ PCI`/US93/08107 The HLB of 17 or less is not essential to the permeability enhancement of all structural classes of surfactants. For example, the nonionic surfactant polysorbate-80 (Tween-80; POE-sorbitan-monooleate) having an HLB of 15 is not a permeability enhancer in the phenol red perfusion test. For the POE-sorbitan esters, the HLB for 5 permeability enhancement is less than 15; surfactants of this structural class with an HLB of greater than about 15 are not permeability enhancers. In yet another structural class, Gelucire 44/14, with an HLB of 14, is not a permeability enhancer, but is an effective peptide protecting agent. Examples of nonionic surfactants which are peptide protecting agents but are not permeability enhancers are NP-POE-30 (Igepal C0-880), 10 NP-POE-50 (Igepal C0-970), NP-POE-100 (Igepal CO-990), Gelucire 44/14, and polysorbate-80.
In a typical embodiment of the invention, a soft gelatin capsule contains 50 mg of the active agent, 640 mg oil (Capmul-MCM), and 160 mg surfactant (polysorbate 80).
In another typical embodiment, a #00 hard gelatin capsule contains 50 mg drug and 15 650 mg surfactant (Gelucire 44/14). The quantity of surfactant or surfactant plus oil in a dosage form of this invention can vary widely. However, a single unit dosage form will contain from about 1 mg to about 500 mg of the active agent, and from about 25 mg to about 1000 mg surfactant or surfactant plus oil.
The following Examples illustrate the invention.
The chymotrypsin inhibition by surfactants was demonstrated in vitro with respect to terlakiren. Control solutions were made of 0.06 mM terlakiren in isotonic buffer. A chymotrypsin solution in 0.001 N hydrogen chloride was added to give a final chymotrypsin concentration of 0.25 ~M or 2.5,uM. The initial concentration of terlakiren 25 and its concentration at various time points were analyzed by HPLC. Test solutions containing 1 % and 5% by weight surfactant and 0.06 mM terlakiren in isotonic buffer were made and the above chymotrypsin solutions were added. The concentrations ofterlakiren before and during the reaction were analyzed, as summarized in Table 1. The initial rate of the degradation was determined by the slope of concentration vs. time 30 plot.
WO 94/07472 214 ~ 7 6 3 PCI/US93/08107 Table I
Initial % Inhi- Terla-Chymo- Rate bition kiren trypsin Initial Ratio [100% x remain-Concen-Rate (Sur- (1-lnitial ing Control vs. tration ~uM/ factanV Rate after SurfactantHLB ~um) min) Control) Ratio)] 30 min.
Control 0.251.85 0.23 77 36 1% NP-POE- 14.0 0.250.42 85 10.5 Control 0.251.90 0.31 69 34 1% NP-POE-50 18.3 0.250.59 76 Control 0.252.10 32 1% poly- 15 0.250.65 0.31 69 73 sorbate 80 5% poly- 15 0.250.33 0.16 84 87 sorbate 80 Control 0.252.09 91 32 1% Gelucire 14 0.250.18 0.09 92 Control 0.251.82 36 1% PEG 400 20 0.251.84 1.00 0 37 5% PEG 400 0.251.55 0.85 15 42 Control 2.515.4 <2 1% poly- 15 2.53.54 0.23 77 9 sorbate 80 Control 2.512.2 89 <2 5% poly- 15 2.51.39 0.11 51 sorbate 80 Control 2.514.7 <3 5% Brij 35 16.9 2.51.08 0.07 93 57 Control 2.514.1 <3 5% Myrj 52 16.9 2.51.07 0.08 92 61 E)CAMPLE 2 A standard procedure was employed to assess the in vitro potency of 40 surfactants mixed with oils, which formed emulsions when mixed with water, vs WO 94/07472 2 ~ ~ ~ 7 6 3 PCr/US93/08107 chymotrypsin degradation of terlakiren. Terlakiren was dissolved in acetonitrile and added to a solution or dispersion of excipients (at concer,l, alions of 0.2 or 1 %, gm/100 ml) in a pH 6.5 isotonic citrate-phosphate buffer. The drug (0.065 mM) concentration was assayed. Chymotrypsin was then added to start the reaction. The solution was5 placed into a 37C water bath and sampled at 5, 10, 15, 20, 25, 30, 35, 40, and 45 minutes. The reaction was quenched using the pH 2.5 mobile phase. The samples were then assayed by reverse phase high performance liquid chromatography of terlakiren using a Water Novapak C-18 column. The mobile phase was a water:
acetonitrile (50:50) mixture to which was added 1 ml of phosphoric acid per liter.
The results in Table ll demonstrate that the oil/surfactant emulsions reduced the chymotrypsin-catalyzed degradation of terlakiren.
The emulsion vehicles tested were:
Vehicle A: Capmul-MCM/Polysorbate-80 (80/20) Vehicle B: Capmul-MCM/Miglyol-812/Polysorbate-80 (40/40/20) Vehicle C: Capmul-MCM
Vehicle D: Capmul-MCM/Polysorbate-80/Ethanol (57/38/5) Table ll Inhibition %
[100% x Terlakiren InitialInitial Rate(1-lnitial Remaining Vehicle/Chymotrypsin Rate Ratio Rate a~ter30 Control ~M) ~uM/min)(Inh/Control)Ratio)] minutes Control 0.25 1.9 41 25 0.2% A 0.25 0.045 0.023 98 98 1% A 0.25 0.040 0.021 98 98 Control 0.25 1.9 41 0.2% B 0.25 0.068 0.035 96 95 1% B 0.25 0.098 0.051 95 95 30 Control 0.25 1.9 41 0.2% C 0.25 0.55 0.28 71 82 Control 0.25 2.6 41 1% D 0.25 0.034 0.013 99 98 ~ 576~
WO 94/07472 PCr/US93/08107 Experiments to determine the bioavailability of terlakiren in dogs in this Example and Examples 4 to 10 were conducted in the following manner. Beagle dogs were orally dosed with terlakiren c~rsules, followed by gavage with 150 ml H2O. Serum5 levels of terlakiren were measured at six time points post-dose: 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, and 4 hours. Each dog served as its own control on a precedi"g week. Serum was extracted with N-butyl chloride followed by incubation with an aqueous solution of chymotrypsin. The degradation product wasassayed, after derivitization with fluorescamine. The fluorescence detector was a 10 Spectroflow 280. The column was Novapak C-18. The emission wavelength was 380nm. The mobile phase was 75:25 water:acetonitrile and flow rate 1.0 ml/minute. The detection limit was 10 ng/ml. As a measure of drug bioavailability, zero-to-four-hour areas under curves (AUC) were calcul~tecl from the concentration-vs-time plots for each dog using the trapezoidal rule.
Terlakiren (0.5053 g) was dissolved in 100% ethanol, and the solution was then added to molten Gelucire 44/14 (6.53 g) with stirring. Gelucire is a mixture of glyceryl and polyethylene glycol (PEG) 1500 esters of fatty acids from palm kernel oil, having a melting point of 44C and an HLB of 14. This mixture was heated at 50C to remove ethanol from the mixture to obtain a clear solution of 7.18% by weight terlakiren in 20 Gelucire 44/14. Capsules (#00) were each filled with 700 mg of the Gelucire 44/14 solution. Two capsules (100 mg of terlakiren) were dosed in each of the 4 dogs.
Blood levels of the drug over 4 hours postdose were analyzed. The area-under-the-curve (AUC) of each dog's blood level was cP~Iu ~l~ted and compared with that of a 100 mg powder-filled c~psule in the same dog. The average improvement in bioavailability 25 of this formulation over the solid capsules was 22 fold.
Terlakiren (one part) was mixed and milled with molten Gelucire (5 parts) in an Attritor mill for 5 hours to give a homogeneous dispersion. Hard gelatin capsules (#0) were filled with 600 mg of the dispersion which contained 100 mg of terlakiren. In a 30 group of 4 dogs (2 males and 2 females), each dog was dosed with one capsule.The average improvement in bioavailability due to Gelucire 44/14 was 21 fold, compared to powder-filled capsule.
W0 94/07472 2 ~ 4~7 ~3 ~ ` ` PCI/US93/08107 -1~
By a process similar to the one described in Example 4, 100 mg of terlakiren was mixed with 500 mg of Myrj 52 and filled into #0 capsules. Myrj 52 is a mixture of polyoxyethylene mono-esters and di-esters of stearic acid, the average polymer length 5 being about 40 oxyethylene units. The AUC's of 4 dogs were compared. The average improvement in bioavailability due to Myrj 52 was 14 fold, compared to powder-filled capsule.
By a process similar to the one described in Example 4, 100 mg of terlakiren 10 was mixed with 500 mg of Acconon 1000 ML and filled into #0 capsules. AccononPEG 1000 ML is PEG (1,000 molecular weight) ethoxylated lauric acid, having a melting point of 37.3C and an HLB value of 16.5. The AUC's of 4 dogs were compared. Theaverage improvement in bioavailability due to Acconon 1000 ML was 10 fold, compared to powder-filled capsules.
Terlakiren (1 part) and Gelucire 44/14 (5 parts) were mixed and milled in a Dynomill for 8 minutes to give a homogeneous dispersion. The particle size of terlakiren was greatly reduced. Capsules containing 600 mg of this dispersion (100 mg terlakiren) were tested in both dogs and humans. The improvements in bioavailability 20 due to Gelucire 44/14 are 14 fold in 4 dogs and 2.8 fold in 11 healthy volunteers, compared to powder-filled capsules.
Terlakiren (1 part) and Gelucire 44/14 (5 parts) were mixed and homogenized without any particle size reduction to give a homogeneous dispersion. Capsules 25 containing 600 mg of this dispersion (100 mg terlakiren) were tested in both dogs and humans. The improvement in bioavailability due to Gelucire 44/14 were 1.7 fold in 4 dogs and 2.3 fold in 11 healthy human volunteers, compared to powder-filled capsules.
Formulations of terlakiren in surfactants mixed with oils, which formed emulsions 30 when mixed with water, were administered to dogs. Each dog received a 100 mg dose of terlakiren.
W094/07472 ~ 763 PCr/US93/08107 Tables lll and IV give the content of the formulations including the control "powder-filled capsule formulation (Powder) which does not contain protective surfactants.
JTable V presents the mean AUC for each formulation and the mean fold-5 improvement over the powder-filled capsule.
Table lll Formulations of Terlakiren in a Surfactant and in Mixtures of Oils with Surfactants (mg per unit dosage form) Component CPE C CP CMPPowder Terlakiren 50 50 50 33.3 100 Capmul MCM 426 600 640 386.7 polysorbate 80 284 - 160 193.3 ethanol 40 Migylol 812 -- -- -- 386.7 lactose - - - - 80 croscarmellose - - - - 12 sodium Na lauryl sulfate - - - - 2 Mg stearate - - - - 6 capsule size ~00~11.5 #14 i~16 X2 gelatin shellhard soft soft soft hard WO 94/07472 2 ~ ~ ~ 7 6 3 PCr/US93/08107 Table IV
Formulations of Terlakiren Containinq Mixtures of Oil and Surfactant (in mg per unit dosage form) 1, 5 Component SoyLab MigPS80 MigLab CapOlPS8 Powder o Terlakiren 50 50 50 50 100 Miglyol 812 - 420 366 Soybean Oil 365 Labrafil 5 - 4 Polysorbate 80 - 170 - 100 Capmul MCM - - - 195 Oleic Acid - - - 195 Lactose - - - - 80 15croscarmellose - - - - 12 sodium Na lauryl - - - - 2 sulfate Mg stearate - - - - 6 20capsule size #0 ~0 #0 ~00 ~2 gelatin shell hard hard hard hard hard Table V
4 Bioavailability of Terlakiren in Beaqle Do~qs Followinq Oral 5Adlll;llisllalion of a 100 m~q Dose Formulation No. of Dogs Mean AUC (mcg Mean Fold-hr ml-1) Improvement CPE 12 0.312 12.5 C 12 0.258 11.7 CP 12 0.296 11.2 CMP 12 0.443 20.8 SoybLab 4 0.105 3.5 MigPS80 4 0.275 10.3 15MigLab 4 0.243 8.2 CapOlPS80 4 0.596 25.2 Powder 12 0.086 1.0 20Formulations of terlakiren in surfactants mixed with oils, which formed emulsions when mixed with water were also ad" ,i"i~lered to human volunteers. The compositions of the formulations were the same as those shown in Table lll. Eachvolunteer received a 100 mg dose of terlakiren. The AUC results are given in Table Vl.
The results show that surfactants mixed with oils yielded an improvement in 25 bioavailability of terlakiren relative to the powder-filled capsules containing none of the protecting agents.
WO 94/07472 ~ ~ 5 ~ 63 ` PCI/US93/08107 Table Vl Bioavailability of Terlakiren in Human Volunteers Followinq Oral Adl"i~ lion of a 100 mq Dose in Four Different Formulations Formulation No. of Subjects Mean AUC/ng hr Mean Fold-ml-1 Improvement*
C 12 4.58 6.3 CP 12 4.39 6.2 CMP 12 5.90 8.5 Powder 12 0.82 1.0 * Only 11 of the subjects were included in this calculation, since in one subject no serum levels of terlakiren were detected following ad,,,i,,i~ lion of the powder-filled capsule.
The in vitro trypsin inhibition by surfactants was assessed with benzoyl-arginine-para-nitroanilide (BAPNA) as the enzymatically labile active agent. Test solutions of 1.25 ~g/ml trypsin (103 benzoyl arginine ethyl ester units/ml), 0.5 mg/ml BAPNA, and 0.5 mg/ml surfactant were prepared in a buffer of 0.048 M TRIS and 0.019 M calcium chloride having a pH of 8 and containing 3.75 ~g/ml bovine serum albumin. These test solutions were incubated at 37C.
Samples were taken after 5 minutes and then at 5 minute intervals to 40 minutes, and quenched with an equal volume of 30% by volume of acetic acid before analysis. The decay product of BAPNA hydrolysis, 4-nitroaniline, was analyzed with a Perkin-Elmer Lambda 3B UV/Vis spectrophotometer. The absorbance of the quenched samples was measured at 410 nm.
The percentage inhibition of BAPNA degradation was calculated based on a co"".arison with a control which did not contain a surfactant, as follows:
% inhibition = 100% x l1 -(SISO)] wherein Sj is the rate of change of absorbancewith time in the presence of a surfactant, and SO is the rate of change of absorbance with time in the absence of a surfactant.
The results in Table Vll demonstrate that the tested surfactants reduced the trypsin-catalyzed degradation of BAPNA.
W O 94/07472 2 ~ 4 5 7 6 3 ` PC~r/US93/08107 Table Vll REDUCTION OF TRYPSIN - CATALYZED DEGRADATION
OF BAPNA BY SURFACTANTS
Initial Rate Ratio Rate x 103 (SurfactanV
CGIII,~OSjtiOll(~ A/~. min.) Control) % Inhibition Control 8.25 BRIJ35 0.2% 7.01 0.850 15 BRIJ35 1% 3.98 0.482 52 ********AA*A*************************
Control 8.25 Polysorbate 80 0.2% 7.02 0.850 15 Polysorbate 80 1% 4.38 0.530 47 *****A~**AAAAAA*AAAAA**AAA~*********************************************
Control 8.25 MYRJ 52S 0.2% 7.44 0.901 10 MYRJ 52S 1% 5.21 0.631 37 *************************************************** A *AA*****************
Control 8.25 IGEPAL C0-970 0.2% 7.93 0.960 4 IGEPAL C0-970 1% 5.67 0.687 31 25********AA*AA*************************
Control 7.76 Gelucire 44/14 0.2% 6.98 0.898 10 Gelucire 44/14 1% 4.38 0.564 44 WO 94/07472 2 1 ~ ~ 7 ~ 3 PCr/US93/08107 Example 12 The in vitro chymotrypsin inhibition by surfactants was ~sessed with benzolytyrosine ethyl ester (BTEE) as a model for an esterified drug or prodrug the hydrolysis of which is catalyzed by chymotrypsin. Test solutions of 0.6 ,,,icloylGmlm 5 chymotrypsin, 0.43 micromolar BTEE, and 3 or 10 mg/ml surfactant were prepared in a 0.034 M Tris HCI buffer containing 0.43 M calcium chloride having a pH of 7.8. The studies were performed at room temperature.
The progress of the hydrolysis of BTEE was monitored with a Perkin-Elmer Lambda 3B UV/Vis spectrophotometer. The reaction mixture was introduced into a 10 cuvette which was placed into the spectrophometer for direct reading of absorbance at 256 nm as a function of time.
Table Vlll lists the percent of BTEE remaining after 10 minutes and the results demonstrate that the tested surfactants reduced the chymotrypsin-cataiyzed hydrolysis of BTEE.
Tabel Vlll Composition % of BTEE remaining after 10 minutes Control 1 9 Polysorbate 80 0.3% 23 Polysorbate 80 1% 36 Control 1 9 Myrj 52S 0.3% 26 Myrj 52S 1% 37
The co-administration of a pharmaceutically active agent with a surfactant is mentioned in Swenson and Curatolo, Advanced Drug Delivery Reviews, 8, 39-92 (1992).
The surfactant is described as enhancing the permeability of a drug through the intestinal wall.
United States Patent No. 4,579,730 suggests that the ionic bile salt sodium cholate, which is a surfactant, functions as a protease inhibitor in the small intestines so promoting absorption of insulin. The general use of surfactants as protease inhibitors in the gastrointestinal tract is not suggested.
The use of non-surfactant protease inhibitors as protectants against gastrointestinal proteases has been described in Lee, J. Controlled Release, 13(1990)213-223, Ziv et al, Biochem. Pharmacol., 36(1987)1035-1 039, and U.S. Patent 4,579,730. Hayakawa et al, Life Sciences 45,167-174(1989), reports that the bile salt sodium glycocholate and the nonionic surfactant polyoxyethylene-9-lauryl ether either inhibit or stimulate degradation of insulin by nasal homogenates, depending on the concentration of the surfactants. European Patent Publication No. 33~ discloses that the protease activity of vaginal washings is decreased in the presence of the anionic surfactant sodium dodecyl sulfate and also discloses a method of vaginalcoadministration of an ionic or nonionic surfactant with a biologically active polypeptide to inhibit vaginal protease at the site of adl"ini~ lion.
In accordance with the invention, pharmaceutical compositions for oral administration are provided comprising an enzymatically labile pharmaceutically active agent which is permeable through the intestinal wall and at least one nonionic surfactant which is capable of protecting said active agent against deactivation by enzymes.
In one embodiment of the invention, the active agent tS a peptide having a molecular weight of less than about 3,000. Examples of suitable nonionic surfactants are ethoxylated alcohols, ethoxylated fatty acids, sorbitan derivatives and ethoxylated 2 ~ 1 ~ 5 7 ~ 3 - PCI/US93/08107 alkyl phenols, specifically ethoxylated lauric acid, polyoxyethylene(40)stearate, polyoxyethylene(20)sorbitan monooleate, polyoxyethylene(23)1auryl ether, nonylphenoxypoly(ethyleneoxy)ethanol-30, nonylphenyoxypoly(ethyleneoxy)ethanol-50, or a mixture of glylceryl and polyethylene glycol-1500 esters of paim kernel oil.
In another embodiment of the invention, an oil is included in the composition.
i-xamples of suitable oils are monoglycerides, e.g., mono-octanoin or monodecanoin, digiycerides, e.g., glyceryl-1,2-dioctanoate, and triglycerides, e.g., vegetable oil or caprylic/capric triglyceride.
The invention also provides a pharmaceuticai composition for orai administrationcomprising (1 ) an enzymatically labile pharmaceutically active agent which is permeable through the intestinal wall only in the presence of an intestinal permeability enhancer, (2) at least one nonionic surfactant which is capable of protecting said active agent against deactivation by proteolytic enzymes and which is not an intestinal permeability enhancer, and (3) an intestinal permeability enhancer which is other than said nonionic surfactant. In one embodiment, this composition comprises a nonionic surfactant having an HLB of about 14 to about 20.
The invention also provides a pharmaceuticai composition for orai acJI~ ,i"isl~ alion comprising (1) an enzymatically labile pharmaceutically active agent which exerts its therapeutic activity locally in the stomach or intestine, and (2) at least one nonionic sur~actant which is capable of protecting said active agent against deactivation by enzymes.
The invention further provides a method for inhibition of the enzymatic degradation of an enzymatically labile pharmaceutically active agent which is permeable through the intestinal wall by combining said active agent with a nonionic surfactant which is capable of protecting said active agent against deactivation by enzymes.
The invention also provides a method for the oral administration of an enzymatically labile pharmaceutically active agent which is permeable through the intestinal wall to a host which comprises co-administering to said host said active agent and at least one nonionic surfactant capable of protecting said active agent against deactivation by enzymes.
The invention yet further provides for a method for the oral administration of an enzymatically labile pharmaceutically active agent which is permeable through the intestinal wall only in the presence of an intestinal permeability enhancer by co-WO 94/07472 2 1 4 5 7 6 3 PCI~/US93/08107 administering to said host said active agent, at least one nonionic surfactant which is c~p~hle of protecting said active agent against deactivation by enzymes and which is not an intestinal permeability enhancer, and an intestinal permeability enhancer which is other than said nonionic surfactant.
The enzymatically labile pharmaceutically active agents of the invention containenzymatically labile bonds, such as ester, amide and/or peptide bonds, and are inactivated by digestive enzymes in the gastrointestinal tract. Examples of suchdigestive enzymes are pepsin, trypsin, chymotrypsin, elastin, aminopeptidase, carboxypeptidase, lipase and intestinal glycosid~es and esterases.
Examples of enzymatically labile pharmaceutically active agents (the active agents) are calcitonin, prolactin, adrenocorticotropin, thyrotropin, growth hormone, gonadotropic hormone, oxytocin, vasopressin, gastrin, tetragastrin, pentagastrin, glucagon, insulin, secretin, substance P, gonadotropin, leutinizing hormone releasing hormone, leuprolide, enkephalin, follicle stimulating hormone, cholecystokinin, thymopentin, endothelin, neurotensin, i"te"eron, interleukins, insulinotropin, and therapeutic antibodies; and analogues of the above agents, which possess D-aminoacids, blocked amino or carboxyl end groups e.g., nafarelin acetate and YdAGFdL (an enlaphalin analogue), and non-natural amino acids such as S-methyl cysteine and statine. Also included are purified extracts of natural origin and their chemical modifications, as well as products obtained by tissue culture and products obtained by cultivating microorganisms or cells rendered productive by genetic engineering techniques. Also included are synthetic peptides and derivatized synthetic peptides such as terlakiren (isopropyl-N-[N-(4-morpholine-carbonyl)-L-phenylalanine-S-methyl-cysteine]-2(R)-hydroxy-3(S)-amino-4-cyclohexylbutanoate) disclosed in U.S. Patent 4,814,342, Example 4 thereof, which is incorporated herein by reference. Furtherincluded are prodrugs of the active agents, i.e., derivatives of the active agent which convert to the active agent in vivo.
The active agents further include prodrugs of a pharmaceutically active compound which itself may not contain an enzymatically labile bond. Such prodrugs are themselves enzymatically labile by connection of the prodrug group to the pharmaceutically active compound through an enzymatically labile bond such as anester or amide bond.
WO 94/07472 . ~ 1 4 5 7 6 3 ; PCI`/US93/08107 According to the invention, when the active agent is permeable through the intestinal wall, it is co-administered with at least one nonionic surfactant which is capable of protecting the active agent against deactivation by enzymes. The nonionic surfactant is used in an amount which is effective in protecting the active agent against deactivation by enzymes.
In general, an active agent or prodrug is considered permeable through the intestinal wall if it can permeate the intestinal wall without the aid of a permeability enhancer. The intestinal permeability of the enzymatically labile active agent or prodrug is determined by perfusion of a solution of the active agent or prodrug through a segment of the intestine of an anesthetized rat. This test must be carried out in the absence of digestive enzymes to reduce enzymatic degradation of the tested active agent or prodrug. The intestinal segment therefore must be properly washed before the test or the test must be in the presence of inhibitors of digestive enzymes, such as Bowman-Birk trypsin/chymotrypsin inhibitor.
For the purposes of the invention, the enzymatically labile active agent or prodrug is considered permeable through the intestinal wall when it has a P pp greater than about 3.5 X 10 6 cm/sec. The P pp of a compound may be determined from the following equation:
KA = A X P~l~r (1 ) V' wherein KA jS the absorption rate constant of the compound, A jS the surface area of the intestinal segment, and V is the volume of the intestinal segment. When the intestinal segment is cylindrical and the intestinal radius is about 0.2 cm, as in the rat, A/V is about 10 cm~'.
The absorption rate constant KA for a compound is calculated in the rat intestinal permeability test from the following equation:
KA = Q(1-CJC;) (2) V
30 wherein Cj is the concentration of the compound at the start of the test, C0 is the concentration of the compound in the perfusate after passage through a 22 cm intestinal segment, Q jS the flow rate and V is the volume of the intestinal segment, as mentioned above.
WO 94/07472 ~ 1 4 5 7 6 3 PCI/US93/08107 Terlakiren is an example of an enzymatically labile drug which has good intestinal permeability, and does not require a permeability enhancer to achievesignificant oral absorption. Terlakiren has a KA Of 0.02 min-1, a P pp of 3.3 x 1 0 5 cm/sec, , and an aqueous solubility of 0.08 mg/ml.
Friedman and Amidon, Pharmaceutical Research, 8,93-96 (1990), as~esses the permeability of the pentapeptides Leu-enkephalin and Leu-D(Ala)2-enkephalin using the rat intestinal perfusion model. Analysis of the data in the reference using the above equations (1 ) and (2) results in a P~pp value of 1.3 X 10-3 cm/sec for both enkephalins.
These compounds are thus permeable under the definition of permeability of the invention. These compounds are also enzymatically labile. An example of an enzymatically labile compound which is impermeable under the above definition ofpermeability according to the invention is insulin having a P pp of 4.97 X 10-7 cm/sec.
In general, the coadministration of nonionic surfactants with an enzymatically labile pharmaceutically active agent or prodrug will protect the agent or prodrug from enzymatic hydrolysis when the surfactant and the agent or prodrug are coadministered orally, rectally, nasally, or vaginally.
Examples of permeable active agents are peptides with a molecl l15~r weight of less than about 3,000 and more than about 200, which are passively absorbed by the intestinal wall, and dipeptides having a molecular weight of about 200, which are actively transported. As the polarity of the peptide decreases, its permeabilityincreases. However, above a molecular weight of about 2000 to about 3000, permeation will not generally occur without the aid of a permeability enhancer. Specific examples of peptides having a molecular weight of less than about 2,000 and therefore being permeable, are oxytocin, vasopressin, leutinizing hormone releasing hormone, leuprolide, enkephalin, thymopentin, octreotide, thyrotropin releasing hormone, CCK-8, bradykinin, angiotensin 1, somatostatin, desmopressin, substance P, and gonadotropin releasing hormone. Specific examples of peptides having a molecular weight of about 3,000, and therefore being slowly permeable, are calcitonin, glucagon, secretin,endorphin, and insulinotropin.
Examples of active agents which exert their therapeutic activity locally in the stomach or small intestine are anti-ulcer medications such as ~ucralfate, cholesterol lowering agents such as cholestyramine, hormones such as gastrin and cholecystokinin, antibiotics and other therapeutic agents.
WO 94t07472 ~ 1 4 5 7;6~`3 PCr/US93/08107 I . ~,. . . ..
Those surfactants which are capable of protecting the active agent against deactivation by enzymes (protective surfactants) may be identified by an in vitro enzyme inhibition assay as described in Examples 1, 2 and 11.
Examples of more preferred protective nonionic su~factants are as follows:
Chemical Descli~lion ¦ Example ¦ HLB
Sucrose Faffy Acid Ester Sucrose monolaurate Ryoto Sugar Ester LWA 1540 15.0 Sucrose monooleate Ryoto Sugar Ester OWA 1570 15.0 Sucrose monopalmitate Ryoto Sugar Ester P157015.0 Sucrose monostearate Ryoto Sugar Ester S157015.0 Sorbitan Derivatives POE (20) sorbitan monooleate Tween 80 15.0 POE (20) sorbitan monostearate Tween 60 14.9 POE (20) sorbitan monolaurate Tween 20 16.7 15 Ethoxylated Faffy Acids POE (40) stearate Myrj-52 16.9 glyceryl and PEG 1500 esters of Gelucire 44/14 14.0 fatty acids from palm kernel oil Ethoxylated lauric acid Acconon 1000 ML 16.5 20 Ethoxylated Alcohols POE (23) lauryl ether ¦ Brij-35 ¦ 16.9 Ethoxylated Alkyl Phenols Nonylphenoxypoly(ethyleneoxy)- Igepal C0-970 18.3 ethanol Igepal CO-710 14.0 25 Miscellaneous Saturated polyglycolyzed glyceride ¦ Labrasol ¦ 14 Examples of preferred nonionic surfactants are as follows:
WO 94/07472 ~ i 7 ~ ~ PCr/US93/08107 Chemical Descri~lion Example HLB
Apricot kernel oil PEG-6 complex Labrafil M1944CS 3.0 Polyoxyl 35 castor oil Cremophor EL 12-14 PEG-6 octanoic/decanoic Softigen 767 17 5 glycerides Polyoxyethylated vegetable oil Emulphor EL-620 12 Sorbitan mono-oleate Span 80 4.3 Poloxamers Pluronics 14-20 Polyoxyethylene glycerol TagatTO 11.3 10 trioleate Sorbitan mono-laurate Span 20 8.6 Acetoglycerides Myvacets 3.8-4.0 Decaglycerol mono/dioleate Caprol PGE860 11 Polyoxyethylene(4)1auryl ether Brij 30 9 5 POE 9 mono-oleate Pegosperse 400 MO 11 POE (20) sorbitan trioleate Tween 85 11 POE (4) sorbitan monolaurate Tween 21 13.3 Mono/diglycerides of Imwitor-742; Capmul-MCM 5.5-6 octanoic/decanoic acids Glycerol Mono-oleate Capmul-GMO 3.4 Mono-octanoin Imwitor-308 6 An oil may be coadministered with the active agent and the protective nonionic surfactant. In the context of the invention, an oil is a liquid which is il,lrlliscible with 25 water. The oil may aid in solubilization of the active agent where the active agent is non-polar. In some cases, the oil may also be a protective surfactant, for instance Capmul-MCM (monooctanoin). Other suitable oils include triglycerides, diglycerides, and monoglycerides. The monoglycerides, e.g., mono-olein, and mono-octanoin (Capmul MCM; Imwitor-308), are unusual in that they are polar oils, compared to di-30 and tri-glycerides, and, can also be surfactants or emulsifiers. The monoglycerides may serve as emulsifiers when mixed with non-polar oils such as triglyceride vegetable oils or medium chain C4-C12 triglycerides such as Miglyol-812. When the monoglyceride WO 94/07472 ~ ~L 4 ~ PCr/US93/08107 is the protective surfactant of the formulation, the monoglyceride serves as the water-immiscible oil phase. In that case, an additional surfactanVemulsifier may be included to emulsify the monoglyceride oil in the aqueous use environment. When an additional surfactanVemulsifier is not present, the monoglyceride can serve both as oil phase and 5 surfactanVemulsifier. For example, when mono-octanoin (Capmul-MCM) is released in an aqueous use environment, it serves both as an oil and a surfactanvemulsifler.Suit~hle combinations of surfactant and oil include Tween-80 with Miglyol-812 or Capmul-MCM, and Labrafil-M-1944CS with Miglyol-812. Mixtures of more than twosurfactants and oils are possible. For example, Tween-80 and Capmul-MCM may be 10 combined with Miglyol-812.
Suitable oils for use in this invention are:
Example Chemical Description Miglyol 812 Octanoic/Decanoictriglyceride Soybean oil Vegetable oil Sesame oil Vegetable oil Olive oil Vegetable oil Oleic acid Fatty acid Imwitor-308 Mono-octanoin Imwitor 742; Capmul-MCM Mono/di-glyceride of octanoic and decanoic acids Lipiodol lodinated vegetable oil Capmul-GMO Glycerol mono-oleate According to the invention, an active agent, which is permeable through the intestinal wall only in the presence of an intestinal permeability enhancer (non-25 permeable active agent) is co-administered with at least one protective nonionic surfactant which is not a permeability enhancer (non-enhancer protective surfactant), and a permeability enhancer which is not the protective nonionic surfactant.
In general, non-permeable active agents do not disappear from the perfusion fluid after about one hour in the above described permeability test. Examples of such 30 active agents are peptides of a molecular weight of more than about 3,000, e.g., prolactin, growth hormone, insulin, gonadotropin, follicle stimulating hormone, interferons, interleukins and therapeutic antibodies.
The ability of a nonionic surfactant to enhance the permeability of a non-permeable active agent may be determined by the following test. A segment of theintestine of an anesthetized rat is externalized, and a solution of the poorly absorbed drug phenol red and the nonionic surfactant to be tested is pumped through the 5 intestinal segment for one hour. At the end of the one hour perfusion, systemic blood is collected and the drug concentration therein is measured, e.g., by high performance liquid chromatography. This test was applied to a series of nonionic nonylphenoxypoly-oxyethylene (NP-POE) surfactants having from 9 to 100 POE units. These surfactants have the non-polar NP segment and the polar POE segment. The more oxyethylene 10 (OE) units, the more polar the surfactant. It was found that the less polar surfactants having 9 to 20 OE units are permeability enhancers, whereas the more polar surfactants having 30 to 100 OE units are not. This is illustrated in Table A, which presents plasma phenol red levels at the end of a one hour rat intestinal perfusion with phenol red in the presence of 1% (gm/100 ml) NP-POE-9, -10.5,-20,-30,-50,-100.
Table A
PLASMA PHENOL RED
NP-POE ADDED HLBCONCENTRATION (MCG/ML) NONE - 0.35 NP-POE-9 13.4 22.49 NP-POE-10.5 14.0 31.06 NP-POE-20 16.3 25.47 NP-POE-30 17.4 0.24 NP-POE-50 18.3 0.15 NP-POE-100 19.1 0.42 One method of measuring the polarity of nonionic surfactants is by determining the hydrophile-lipophile balance (HLB), Griffin, J. Soc. Cosmet. Chem., 5, 249-256 (1954). For NP-POE's, those surfactants having an HLB of less than 17 are permeability 30 enhancers and those having an HLB of more than 17 are not. Similarly, for mixtures of NP-POE's of different POE lengths, the HLB of 17 or less is essential for permeability enhancement.
W0 94/07472 ~ 3: i ~ PCI`/US93/08107 The HLB of 17 or less is not essential to the permeability enhancement of all structural classes of surfactants. For example, the nonionic surfactant polysorbate-80 (Tween-80; POE-sorbitan-monooleate) having an HLB of 15 is not a permeability enhancer in the phenol red perfusion test. For the POE-sorbitan esters, the HLB for 5 permeability enhancement is less than 15; surfactants of this structural class with an HLB of greater than about 15 are not permeability enhancers. In yet another structural class, Gelucire 44/14, with an HLB of 14, is not a permeability enhancer, but is an effective peptide protecting agent. Examples of nonionic surfactants which are peptide protecting agents but are not permeability enhancers are NP-POE-30 (Igepal C0-880), 10 NP-POE-50 (Igepal C0-970), NP-POE-100 (Igepal CO-990), Gelucire 44/14, and polysorbate-80.
In a typical embodiment of the invention, a soft gelatin capsule contains 50 mg of the active agent, 640 mg oil (Capmul-MCM), and 160 mg surfactant (polysorbate 80).
In another typical embodiment, a #00 hard gelatin capsule contains 50 mg drug and 15 650 mg surfactant (Gelucire 44/14). The quantity of surfactant or surfactant plus oil in a dosage form of this invention can vary widely. However, a single unit dosage form will contain from about 1 mg to about 500 mg of the active agent, and from about 25 mg to about 1000 mg surfactant or surfactant plus oil.
The following Examples illustrate the invention.
The chymotrypsin inhibition by surfactants was demonstrated in vitro with respect to terlakiren. Control solutions were made of 0.06 mM terlakiren in isotonic buffer. A chymotrypsin solution in 0.001 N hydrogen chloride was added to give a final chymotrypsin concentration of 0.25 ~M or 2.5,uM. The initial concentration of terlakiren 25 and its concentration at various time points were analyzed by HPLC. Test solutions containing 1 % and 5% by weight surfactant and 0.06 mM terlakiren in isotonic buffer were made and the above chymotrypsin solutions were added. The concentrations ofterlakiren before and during the reaction were analyzed, as summarized in Table 1. The initial rate of the degradation was determined by the slope of concentration vs. time 30 plot.
WO 94/07472 214 ~ 7 6 3 PCI/US93/08107 Table I
Initial % Inhi- Terla-Chymo- Rate bition kiren trypsin Initial Ratio [100% x remain-Concen-Rate (Sur- (1-lnitial ing Control vs. tration ~uM/ factanV Rate after SurfactantHLB ~um) min) Control) Ratio)] 30 min.
Control 0.251.85 0.23 77 36 1% NP-POE- 14.0 0.250.42 85 10.5 Control 0.251.90 0.31 69 34 1% NP-POE-50 18.3 0.250.59 76 Control 0.252.10 32 1% poly- 15 0.250.65 0.31 69 73 sorbate 80 5% poly- 15 0.250.33 0.16 84 87 sorbate 80 Control 0.252.09 91 32 1% Gelucire 14 0.250.18 0.09 92 Control 0.251.82 36 1% PEG 400 20 0.251.84 1.00 0 37 5% PEG 400 0.251.55 0.85 15 42 Control 2.515.4 <2 1% poly- 15 2.53.54 0.23 77 9 sorbate 80 Control 2.512.2 89 <2 5% poly- 15 2.51.39 0.11 51 sorbate 80 Control 2.514.7 <3 5% Brij 35 16.9 2.51.08 0.07 93 57 Control 2.514.1 <3 5% Myrj 52 16.9 2.51.07 0.08 92 61 E)CAMPLE 2 A standard procedure was employed to assess the in vitro potency of 40 surfactants mixed with oils, which formed emulsions when mixed with water, vs WO 94/07472 2 ~ ~ ~ 7 6 3 PCr/US93/08107 chymotrypsin degradation of terlakiren. Terlakiren was dissolved in acetonitrile and added to a solution or dispersion of excipients (at concer,l, alions of 0.2 or 1 %, gm/100 ml) in a pH 6.5 isotonic citrate-phosphate buffer. The drug (0.065 mM) concentration was assayed. Chymotrypsin was then added to start the reaction. The solution was5 placed into a 37C water bath and sampled at 5, 10, 15, 20, 25, 30, 35, 40, and 45 minutes. The reaction was quenched using the pH 2.5 mobile phase. The samples were then assayed by reverse phase high performance liquid chromatography of terlakiren using a Water Novapak C-18 column. The mobile phase was a water:
acetonitrile (50:50) mixture to which was added 1 ml of phosphoric acid per liter.
The results in Table ll demonstrate that the oil/surfactant emulsions reduced the chymotrypsin-catalyzed degradation of terlakiren.
The emulsion vehicles tested were:
Vehicle A: Capmul-MCM/Polysorbate-80 (80/20) Vehicle B: Capmul-MCM/Miglyol-812/Polysorbate-80 (40/40/20) Vehicle C: Capmul-MCM
Vehicle D: Capmul-MCM/Polysorbate-80/Ethanol (57/38/5) Table ll Inhibition %
[100% x Terlakiren InitialInitial Rate(1-lnitial Remaining Vehicle/Chymotrypsin Rate Ratio Rate a~ter30 Control ~M) ~uM/min)(Inh/Control)Ratio)] minutes Control 0.25 1.9 41 25 0.2% A 0.25 0.045 0.023 98 98 1% A 0.25 0.040 0.021 98 98 Control 0.25 1.9 41 0.2% B 0.25 0.068 0.035 96 95 1% B 0.25 0.098 0.051 95 95 30 Control 0.25 1.9 41 0.2% C 0.25 0.55 0.28 71 82 Control 0.25 2.6 41 1% D 0.25 0.034 0.013 99 98 ~ 576~
WO 94/07472 PCr/US93/08107 Experiments to determine the bioavailability of terlakiren in dogs in this Example and Examples 4 to 10 were conducted in the following manner. Beagle dogs were orally dosed with terlakiren c~rsules, followed by gavage with 150 ml H2O. Serum5 levels of terlakiren were measured at six time points post-dose: 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, and 4 hours. Each dog served as its own control on a precedi"g week. Serum was extracted with N-butyl chloride followed by incubation with an aqueous solution of chymotrypsin. The degradation product wasassayed, after derivitization with fluorescamine. The fluorescence detector was a 10 Spectroflow 280. The column was Novapak C-18. The emission wavelength was 380nm. The mobile phase was 75:25 water:acetonitrile and flow rate 1.0 ml/minute. The detection limit was 10 ng/ml. As a measure of drug bioavailability, zero-to-four-hour areas under curves (AUC) were calcul~tecl from the concentration-vs-time plots for each dog using the trapezoidal rule.
Terlakiren (0.5053 g) was dissolved in 100% ethanol, and the solution was then added to molten Gelucire 44/14 (6.53 g) with stirring. Gelucire is a mixture of glyceryl and polyethylene glycol (PEG) 1500 esters of fatty acids from palm kernel oil, having a melting point of 44C and an HLB of 14. This mixture was heated at 50C to remove ethanol from the mixture to obtain a clear solution of 7.18% by weight terlakiren in 20 Gelucire 44/14. Capsules (#00) were each filled with 700 mg of the Gelucire 44/14 solution. Two capsules (100 mg of terlakiren) were dosed in each of the 4 dogs.
Blood levels of the drug over 4 hours postdose were analyzed. The area-under-the-curve (AUC) of each dog's blood level was cP~Iu ~l~ted and compared with that of a 100 mg powder-filled c~psule in the same dog. The average improvement in bioavailability 25 of this formulation over the solid capsules was 22 fold.
Terlakiren (one part) was mixed and milled with molten Gelucire (5 parts) in an Attritor mill for 5 hours to give a homogeneous dispersion. Hard gelatin capsules (#0) were filled with 600 mg of the dispersion which contained 100 mg of terlakiren. In a 30 group of 4 dogs (2 males and 2 females), each dog was dosed with one capsule.The average improvement in bioavailability due to Gelucire 44/14 was 21 fold, compared to powder-filled capsule.
W0 94/07472 2 ~ 4~7 ~3 ~ ` ` PCI/US93/08107 -1~
By a process similar to the one described in Example 4, 100 mg of terlakiren was mixed with 500 mg of Myrj 52 and filled into #0 capsules. Myrj 52 is a mixture of polyoxyethylene mono-esters and di-esters of stearic acid, the average polymer length 5 being about 40 oxyethylene units. The AUC's of 4 dogs were compared. The average improvement in bioavailability due to Myrj 52 was 14 fold, compared to powder-filled capsule.
By a process similar to the one described in Example 4, 100 mg of terlakiren 10 was mixed with 500 mg of Acconon 1000 ML and filled into #0 capsules. AccononPEG 1000 ML is PEG (1,000 molecular weight) ethoxylated lauric acid, having a melting point of 37.3C and an HLB value of 16.5. The AUC's of 4 dogs were compared. Theaverage improvement in bioavailability due to Acconon 1000 ML was 10 fold, compared to powder-filled capsules.
Terlakiren (1 part) and Gelucire 44/14 (5 parts) were mixed and milled in a Dynomill for 8 minutes to give a homogeneous dispersion. The particle size of terlakiren was greatly reduced. Capsules containing 600 mg of this dispersion (100 mg terlakiren) were tested in both dogs and humans. The improvements in bioavailability 20 due to Gelucire 44/14 are 14 fold in 4 dogs and 2.8 fold in 11 healthy volunteers, compared to powder-filled capsules.
Terlakiren (1 part) and Gelucire 44/14 (5 parts) were mixed and homogenized without any particle size reduction to give a homogeneous dispersion. Capsules 25 containing 600 mg of this dispersion (100 mg terlakiren) were tested in both dogs and humans. The improvement in bioavailability due to Gelucire 44/14 were 1.7 fold in 4 dogs and 2.3 fold in 11 healthy human volunteers, compared to powder-filled capsules.
Formulations of terlakiren in surfactants mixed with oils, which formed emulsions 30 when mixed with water, were administered to dogs. Each dog received a 100 mg dose of terlakiren.
W094/07472 ~ 763 PCr/US93/08107 Tables lll and IV give the content of the formulations including the control "powder-filled capsule formulation (Powder) which does not contain protective surfactants.
JTable V presents the mean AUC for each formulation and the mean fold-5 improvement over the powder-filled capsule.
Table lll Formulations of Terlakiren in a Surfactant and in Mixtures of Oils with Surfactants (mg per unit dosage form) Component CPE C CP CMPPowder Terlakiren 50 50 50 33.3 100 Capmul MCM 426 600 640 386.7 polysorbate 80 284 - 160 193.3 ethanol 40 Migylol 812 -- -- -- 386.7 lactose - - - - 80 croscarmellose - - - - 12 sodium Na lauryl sulfate - - - - 2 Mg stearate - - - - 6 capsule size ~00~11.5 #14 i~16 X2 gelatin shellhard soft soft soft hard WO 94/07472 2 ~ ~ ~ 7 6 3 PCr/US93/08107 Table IV
Formulations of Terlakiren Containinq Mixtures of Oil and Surfactant (in mg per unit dosage form) 1, 5 Component SoyLab MigPS80 MigLab CapOlPS8 Powder o Terlakiren 50 50 50 50 100 Miglyol 812 - 420 366 Soybean Oil 365 Labrafil 5 - 4 Polysorbate 80 - 170 - 100 Capmul MCM - - - 195 Oleic Acid - - - 195 Lactose - - - - 80 15croscarmellose - - - - 12 sodium Na lauryl - - - - 2 sulfate Mg stearate - - - - 6 20capsule size #0 ~0 #0 ~00 ~2 gelatin shell hard hard hard hard hard Table V
4 Bioavailability of Terlakiren in Beaqle Do~qs Followinq Oral 5Adlll;llisllalion of a 100 m~q Dose Formulation No. of Dogs Mean AUC (mcg Mean Fold-hr ml-1) Improvement CPE 12 0.312 12.5 C 12 0.258 11.7 CP 12 0.296 11.2 CMP 12 0.443 20.8 SoybLab 4 0.105 3.5 MigPS80 4 0.275 10.3 15MigLab 4 0.243 8.2 CapOlPS80 4 0.596 25.2 Powder 12 0.086 1.0 20Formulations of terlakiren in surfactants mixed with oils, which formed emulsions when mixed with water were also ad" ,i"i~lered to human volunteers. The compositions of the formulations were the same as those shown in Table lll. Eachvolunteer received a 100 mg dose of terlakiren. The AUC results are given in Table Vl.
The results show that surfactants mixed with oils yielded an improvement in 25 bioavailability of terlakiren relative to the powder-filled capsules containing none of the protecting agents.
WO 94/07472 ~ ~ 5 ~ 63 ` PCI/US93/08107 Table Vl Bioavailability of Terlakiren in Human Volunteers Followinq Oral Adl"i~ lion of a 100 mq Dose in Four Different Formulations Formulation No. of Subjects Mean AUC/ng hr Mean Fold-ml-1 Improvement*
C 12 4.58 6.3 CP 12 4.39 6.2 CMP 12 5.90 8.5 Powder 12 0.82 1.0 * Only 11 of the subjects were included in this calculation, since in one subject no serum levels of terlakiren were detected following ad,,,i,,i~ lion of the powder-filled capsule.
The in vitro trypsin inhibition by surfactants was assessed with benzoyl-arginine-para-nitroanilide (BAPNA) as the enzymatically labile active agent. Test solutions of 1.25 ~g/ml trypsin (103 benzoyl arginine ethyl ester units/ml), 0.5 mg/ml BAPNA, and 0.5 mg/ml surfactant were prepared in a buffer of 0.048 M TRIS and 0.019 M calcium chloride having a pH of 8 and containing 3.75 ~g/ml bovine serum albumin. These test solutions were incubated at 37C.
Samples were taken after 5 minutes and then at 5 minute intervals to 40 minutes, and quenched with an equal volume of 30% by volume of acetic acid before analysis. The decay product of BAPNA hydrolysis, 4-nitroaniline, was analyzed with a Perkin-Elmer Lambda 3B UV/Vis spectrophotometer. The absorbance of the quenched samples was measured at 410 nm.
The percentage inhibition of BAPNA degradation was calculated based on a co"".arison with a control which did not contain a surfactant, as follows:
% inhibition = 100% x l1 -(SISO)] wherein Sj is the rate of change of absorbancewith time in the presence of a surfactant, and SO is the rate of change of absorbance with time in the absence of a surfactant.
The results in Table Vll demonstrate that the tested surfactants reduced the trypsin-catalyzed degradation of BAPNA.
W O 94/07472 2 ~ 4 5 7 6 3 ` PC~r/US93/08107 Table Vll REDUCTION OF TRYPSIN - CATALYZED DEGRADATION
OF BAPNA BY SURFACTANTS
Initial Rate Ratio Rate x 103 (SurfactanV
CGIII,~OSjtiOll(~ A/~. min.) Control) % Inhibition Control 8.25 BRIJ35 0.2% 7.01 0.850 15 BRIJ35 1% 3.98 0.482 52 ********AA*A*************************
Control 8.25 Polysorbate 80 0.2% 7.02 0.850 15 Polysorbate 80 1% 4.38 0.530 47 *****A~**AAAAAA*AAAAA**AAA~*********************************************
Control 8.25 MYRJ 52S 0.2% 7.44 0.901 10 MYRJ 52S 1% 5.21 0.631 37 *************************************************** A *AA*****************
Control 8.25 IGEPAL C0-970 0.2% 7.93 0.960 4 IGEPAL C0-970 1% 5.67 0.687 31 25********AA*AA*************************
Control 7.76 Gelucire 44/14 0.2% 6.98 0.898 10 Gelucire 44/14 1% 4.38 0.564 44 WO 94/07472 2 1 ~ ~ 7 ~ 3 PCr/US93/08107 Example 12 The in vitro chymotrypsin inhibition by surfactants was ~sessed with benzolytyrosine ethyl ester (BTEE) as a model for an esterified drug or prodrug the hydrolysis of which is catalyzed by chymotrypsin. Test solutions of 0.6 ,,,icloylGmlm 5 chymotrypsin, 0.43 micromolar BTEE, and 3 or 10 mg/ml surfactant were prepared in a 0.034 M Tris HCI buffer containing 0.43 M calcium chloride having a pH of 7.8. The studies were performed at room temperature.
The progress of the hydrolysis of BTEE was monitored with a Perkin-Elmer Lambda 3B UV/Vis spectrophotometer. The reaction mixture was introduced into a 10 cuvette which was placed into the spectrophometer for direct reading of absorbance at 256 nm as a function of time.
Table Vlll lists the percent of BTEE remaining after 10 minutes and the results demonstrate that the tested surfactants reduced the chymotrypsin-cataiyzed hydrolysis of BTEE.
Tabel Vlll Composition % of BTEE remaining after 10 minutes Control 1 9 Polysorbate 80 0.3% 23 Polysorbate 80 1% 36 Control 1 9 Myrj 52S 0.3% 26 Myrj 52S 1% 37
Claims (19)
1. A pharmaceutical composition for oral administration comprising an enzymatically labile pharmaceutically active agent which is permeable through the intestinal wall and at least one nonionic surfactant which is capable of protecting said active agent against deactivation by enzymes.
2. A composition according to claim 1 wherein the active agent is a peptide having a molecular weight of less than about 3,000.
3. A composition according to claim 1 or 2 wherein said nonionic surfactant is an ethoxylated alcohol, an ethoxylated fatty acid, a sorbitan derivative, an ethoxylated alkyl phenol, or a monoglyceride.
4. A composition according to claim 3 wherein said nonionic surfactant is ethoxylated lauric acid, polyoxyethylene(40)stearate, polyoxyethylene(20)sorbitan monooleate, polyoxyethylene(23)1auryl ether, nonylphenoxypoly(ethyleneoxy)-ethanol-30, nonylphenoxypoly(ethyleneoxy)ethanol-50, or a mixture of glyceryl and polyethyleneglycol-1500 esters of palm kernel oil, mono-octanoin, monodecanoin, or mono-olein.
5. A composition according to anyone of claims 1 to 4 wherein an oil is included.
6. A composition according to claim 5 wherein said oil is a monoglyceride, a diglyceride, or a triglyceride.
7. A composition according to claim 6 wherein said triglyceride is a vegetable oil or caprylic/capric triglyceride, said monoglyceride is mono-octanoin or monodecanoin, and said diglyceride is glyceryl-1,2-dioctanoate.
8. A pharmaceutical composition for oral administration comprising (1) an enzymatically labile pharmaceutically active agent which is permeable through the intestinal wall only in the presence of an intestinal permeability enhancer, (2) at least one nonionic surfactant which is capable of protecting said active agent againstdeactivation by enzymes and which is not an intestinal permeability enhancer, and (3) an intestinal permeability enhancer which is other than said nonionic surfactant.
9. A composition according to claim 8 wherein the nonionic surfactant has an HLB of about 14 to about 20.
10. A composition according to claim 9 wherein said nonionic surfactant is an ethoxylated alcohol, an ethoxylated fatty acid, a sorbitan derivative, an ethoxylated alkyl phenol, or a monoglyceride.
11. A composition according to claim 10 wherein said nonionic surfactant is ethoxylated lauric acid, polyoxyethylene(40)stearate, polyoxyethylene(20)sorbitan monooleate, polyoxyethylene(23)lauryl ether, or nonylphenoxypoly(ethyleneoxy)-ethanol-30, nonylphenoxypoly(ethyleneoxy)ethanol-50, a mixture of glyceryl and polyethyleneglycol-1500 esters of palm kernel oil, mono-octanoin, monodecanoin, or mono-olein.
12. A composition according to claim 8 where the active agent is a polypeptide of molecular weight of about 150 to about 150,000.
13. A method for the inhibition of the degradation of an enzymatically labile pharmaceutically active agent which is permeable through the intestinal wall by enzymes which comprises combining said active agent with a nonionic surfactant which is capable of protecting said active agent against deactivation by enzymes.
14. A method according to claim 13 wherein said active agent is a peptide with a molecular weight of less than about 3,000.
15. A method according to claim 13 wherein said nonionic surfactant is an ethoxylated alcohol, an ethoxylated fatty acid, a sorbitan derivative, an ethoxylated alkyl phenol, or a monoglyceride.
16. A method according to claim 13 wherein said nonionic surfactant is ethoxylated lauric acid, polyoxyethylene(40)stearate, polyoxyethylene(20)sorbitan monooleate, polyoxyethylene(23)lauryl ether, or nonylphenoxypoly(ethyleneoxy)-ethanol-30, nonylphenoxypoly(ethyleneoxy)ethanol-50, or a mixture of glyceryl and polyethyleneglycol-1500 esters of palm kernel oil, mono-octanoin, monodecanoin or mono-olein.
17. A method for the oral administration of an enzymatically labile pharmaceutically active agent which is permeable through the intestinal wall to a host which comprises co-administering to said host said active agent and at least onenonionic surfactant capable of protecting said active agent against deactivation by enzymes.
18. A method for the oral administration of an enzymatically labile pharmaceutically active agent which is permeable through the intestinal wall only in the presence of an intestinal permeability enhancer which comprises co-administering to said host said active agent, at least one nonionic surfactant which is capable of protecting said active agent against deactivation by enzymes and which is not anintestinal permeability enhancer, and an intestinal permeability enhancer which is other than said nonionic surfactant.
19. A pharmaceutical composition for oral administration comprising an enzymatically labile pharmaceutically active agent which exerts its therapeutic activity locally in the stomach or intestine, and at least one nonionic surfactant which is capable of protecting said active agent against deactivation by enzymes.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US95596292A | 1992-10-02 | 1992-10-02 | |
| US07/955,962 | 1992-10-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2145763A1 true CA2145763A1 (en) | 1994-04-14 |
Family
ID=25497602
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002145763A Abandoned CA2145763A1 (en) | 1992-10-02 | 1993-09-02 | Pharmaceutical compositions containing nonionic surfactants |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0662826A1 (en) |
| JP (1) | JPH07507565A (en) |
| KR (1) | KR950703333A (en) |
| AU (1) | AU5095393A (en) |
| CA (1) | CA2145763A1 (en) |
| FI (1) | FI934317L (en) |
| HU (1) | HUT69400A (en) |
| IL (1) | IL107084A0 (en) |
| MX (1) | MX9306125A (en) |
| TW (1) | TW253838B (en) |
| WO (1) | WO1994007472A1 (en) |
| ZA (1) | ZA937268B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU1808897A (en) * | 1995-12-13 | 1997-07-03 | Dullatur Limited | A calcitonin preparation |
| SE9602145D0 (en) | 1996-05-31 | 1996-05-31 | Astra Ab | New improved formulation for the treatment of thromboembolism |
| WO2008015959A1 (en) * | 2006-08-01 | 2008-02-07 | Otsuka Pharmaceutical Co., Ltd. | Pharmaceutical composition improved in absorption of pharmacologically active substance |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1090703B (en) * | 1976-12-03 | 1985-06-26 | Scherer Ltd R P | IMPROVEMENT IN USEFUL COMPOSITIONS SUCH AS DRUG VEHICLES |
| JPS6233128A (en) * | 1985-08-07 | 1987-02-13 | Toray Ind Inc | Interferon preparation for enteric oral administration |
| EP0351651B1 (en) * | 1988-07-21 | 1993-09-15 | F. Hoffmann-La Roche Ag | Insulin preparation |
| AU1256692A (en) * | 1991-02-06 | 1992-09-07 | Schering Corporation | Combination of an angiotensin II antagonist or renin inhibitor with a neutral endopeptidase inhibitor |
| WO1993011799A1 (en) * | 1991-12-18 | 1993-06-24 | Pfizer Inc. | Soybean protein or hydrolyzates in pharmaceutical compositions to protect bioactive peptides from enzymatic inactivation |
-
1993
- 1993-09-02 AU AU50953/93A patent/AU5095393A/en not_active Abandoned
- 1993-09-02 WO PCT/US1993/008107 patent/WO1994007472A1/en not_active Application Discontinuation
- 1993-09-02 CA CA002145763A patent/CA2145763A1/en not_active Abandoned
- 1993-09-02 JP JP6509047A patent/JPH07507565A/en active Pending
- 1993-09-02 EP EP93920391A patent/EP0662826A1/en not_active Withdrawn
- 1993-09-02 KR KR1019950701257A patent/KR950703333A/en not_active Application Discontinuation
- 1993-09-10 TW TW082107450A patent/TW253838B/zh active
- 1993-09-23 IL IL107084A patent/IL107084A0/en unknown
- 1993-09-30 HU HU9302774A patent/HUT69400A/en unknown
- 1993-09-30 ZA ZA937268A patent/ZA937268B/en unknown
- 1993-10-01 FI FI934317A patent/FI934317L/en not_active Application Discontinuation
- 1993-10-01 MX MX9306125A patent/MX9306125A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| TW253838B (en) | 1995-08-11 |
| IL107084A0 (en) | 1993-12-28 |
| ZA937268B (en) | 1995-03-30 |
| HU9302774D0 (en) | 1993-12-28 |
| EP0662826A1 (en) | 1995-07-19 |
| AU5095393A (en) | 1994-04-26 |
| HUT69400A (en) | 1995-09-28 |
| FI934317L (en) | 1994-04-03 |
| MX9306125A (en) | 1994-04-29 |
| KR950703333A (en) | 1995-09-20 |
| FI934317A0 (en) | 1993-10-01 |
| WO1994007472A1 (en) | 1994-04-14 |
| JPH07507565A (en) | 1995-08-24 |
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