WO2022251645A1

WO2022251645A1 - Hyaluronidase composition for intravenous administration and method of using the same

Info

Publication number: WO2022251645A1
Application number: PCT/US2022/031357
Authority: WO
Inventors: Solomon S. Steiner
Original assignee: Steiner Ventures Llc
Priority date: 2021-05-27
Filing date: 2022-05-27
Publication date: 2022-12-01

Abstract

Provided are pharmaceutical compositions for intravenous administration comprising hyaluronidase and a vasodilator and methods of treatment and use thereof.

Description

TITLE

HYALURONIDASE COMPOSITION FOR INTRAVENOUS ADMINISTRATION AND METHOD OF USING THE SAME

CROSS REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit of U.S. Provisional Application No. 63/193,851, filed May 27, 2021, the entirety of which is incorporated by reference herein.

BACKGROUND OF THE INVENTION

Field of the Invention

[0002] The present disclosure is directed to a composition for intravenous administration comprising hyaluronidase and a vasodilator and methods of treatment and use of the same. The formulation may be advantageously administered to reduce and remove arterial plaque and/or treat one or more of coronary artery disease, carotid artery disease, atherosclerosis, hypertension, kidney disease and diabetic foot syndrome.

Related Background Art

[0003] The buildup of vascular plaques as people age is well known. It is believed that plaque forms on the inner walls of a person’s arteries as a result of various substances, such as calcium, fat, cholesterol, cellular waste and fibrin, circulating in the blood stream. For example, when cholesterol lodges in the wall of an artery, the body responds with white blood cells that create fatty cellular masses which the artery wall ultimately covers with muscle cells to form a cap covering the fatty cellular mass. This process results in a deleterious narrowing of the arteries and can lead to small unstable plaques that may result in the release of dangerous clots that cause a heart attack. Plaque buildup may also lead to atherosclerosis, i.e., a narrowing and hardening of the arteries, coronary artery disease, carotid artery disease, hypertension, kidney disease and/or diabetic foot syndrome.

[0004] Larger plaques that block or significantly restrict blood flow are often treated by insertion of a stent in the vicinity of the blockage so as to widen the artery. Clearly this is an invasive procedure that would be desirable to avoid. Smaller plaque blockages are often treated through the use of statins or other medications such as ezetimibe to reduce the level of LDL cholesterol in the blood. Such statins include atorvastatin and rosuvastatin, which work by blocking the liver enzyme that promotes cholesterol production in the liver. Ezetimibe works by reducing the adsorption of cholesterol in the intestines. While statins and other medications have been very widely employed, they are required to be taken daily often for the remainder of a patient’s life. In addition, certain patients will discontinue the use of statins due to undesirable side effects.

[0005] Vascular plaques have also been treated by implementing significant lifestyle changes, such as by diet, smoking cessation and/or increased aerobic exercise. While such changes can have a profound impact in some cases, lack of patient compliance remains a significant issue for successful implementation of such lifestyle changes for an extended period of time.

[0006] Hyaluronidases are a well-known family of enzymes that catalyze the degradation of hyaluronic acid. They are classified as hyaluronoglucosidases when their enzymatic mechanism acts to cleave the (l->4)- linkages between N- Acetylglucosamine and glucuronate. It is known that hyaluronan is a constituent of the extracellular matrix and that the catalyzation thereof by hyaluronidase results in increased tissue permeability. As a result, hyaluronidase has been used with other drugs to improve the speed of delivery and dispersion of those drugs. Hyaluronidase has also been used by plastic surgeons who seek to reverse the effects of hyaluronic acid injections.

[0007] Hyaluronidase has also been used to treat atherosclerosis using infusion therapy.

Burgard et al., Intravenose Hyaluronidase-Infusiontherapie, Diabetes, Stoffwechsel and Herz, Band 24, 3/2015. In addition, it has been proposed to use hyaluronidase for the prevention and treatment of cardiovascular diseases, arterial hypertension or cardiac insufficiency. US Patent Pub. No. 2008/0124316 and US Patent Pub. No. 2019/0091302. Heretofore, however, hyaluronidase has not been known to be used to dissolve vascular plaque found in arteries and/or veins.

[0008] Additionally, there remains a need for an improved non-statin treatment of vascular plaque buildup and the deleterious consequences thereof by means of intravenous administration that is effective to dissolve vascular plaque. Such effective administration can also advantageously reduce the need for daily administration of statins and offers an alternative to those individuals that cannot tolerate the undesirable side effects of statins, which can increase patient compliance.

SUMMARY OF INVENTION

[0009] One aspect of the present disclosure is directed to a pharmaceutical composition for intravenous administration, the composition comprising a combination of (i) hyaluronidase; (ii) a vasodilator compatible with the hyaluronidase; and (iii) at least one diluent, wherein the amount of hyaluronidase and the amount of vasodilator in the composition are in combination effective to reduce vascular plaque after intravenous administration to a patient in need thereof. This administration may be performed via multiple infusions over a period of time as disclosed herein.

[00010] Another aspect of the present disclosure is directed to a method for treating one or more conditions resulting from a buildup of vascular plaque in a patient, the method comprising the step of intravenously administering a pharmaceutical composition of the disclosure to the patient in need thereof by IV pump or IV drip.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[00011] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter pertains.

[00012] As used herein, the singular forms “a,” “an,” and “the” include the plural reference unless the context clearly dictates otherwise.

[00013] Except where otherwise indicated, all numbers expressing quantities of ingredients, time periods, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure. At the very least, and not to be considered as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding conventions.

[00014] Additionally, the disclosure of numerical ranges within this specification is considered to be a disclosure of all numerical values and ranges within that range. For example, if a range is from about 1 to about 50, it is deemed to include, for example, 1, 7, 34, 46.1, 23.7, 50 or any other value or range within the range. Moreover, as used herein, the term “at least” includes the stated number, e.g., “at least 50” includes 50.

[00015] “Vascular plaque”, as used herein, refers to plaque buildup on/in the inner walls of the arteries and/or veins of a patient.

[00016] “Compatible vasodilator”, as used herein, refers to a vasodilator that can coexist in a formulation with hyaluronidase for the shelf life of the formulation. In some embodiments, coexisting in a formulation with hyaluronidase for the shelf life of the formulation refers to coexisting without causing significant degradation of hyaluronidase, e.g., less than 10% degradation of its labeled concentration, in some embodiments, less than 5% degradation of its labeled concentration, after storage for one year at 25°C.

Hyaluronidase

[00017] Acceptable forms of hyaluronidase for use in the pharmaceutical compositions of the disclosure include hyaluronidase (active hyaluronidase) selected from the group consisting of bovine hyaluronidase, porcine hyaluronidase, ovine hyaluronidase, and human recombinant hyaluronidase. The hyaluronidase used in the compositions of the disclosure may be a naturally sourced hyaluronidase that is an ortholog of human HYAL5 (PH20). Examples include: VITRASE^® (ovine sourced hyaluronidase available from Bausch + Lomb, Bridgewater, NJ), and AMPHADASE^® (bovine sourced hyaluronidase available from Amphastar Pharmaceutical, Rancho Cucamonga, CA). In some embodiments, the hyaluronidase is human recombinant hyaluronidase produced by genetically engineered Chinese Hamster Ovary (CHO) cells comprising a DNA plasmid encoding for a soluble fragment of human hyaluronidase (PH20). An example of such a human recombinant hyaluronidase is that of SEQ ID NO: 1, which is available under the tradename HYLENEX^® from Halozyme Therapeutics, San Diego, CA, and is a purified hyaluronidase glycoprotein containing 447 amino acids. Forms of hyaluronidase as disclosed, for example, in U.S. Patent Nos. 7,767,429 and 8,431,380, the entirety of each of which is incorporated by reference herein, can be used in accordance with the present disclosure.

[00018] Although manufacturers of hyaluronidase warn against intravenous administration because hyaluronidase is known to rapidly degrade in blood, it has been found that this is not a disadvantage for the compositions and methods described herein. Moreover, it is believed that it may be advantageous for degradation to occur in the blood stream so that the impact of the hyaluronidase is limited to the vascular system. Additionally, the combination of the vasodilator with the hyaluronidase in the compositions and methods of the present disclosure is believed to allow the hyaluronidase to work better than without vasodilator as the hyaluronidase in the compositions of the disclosure can access vascular structures that are particularly difficult to treat, such as arterioles and capillaries.

[00019] When the composition is ready for administration, i.e., the concentrate has been diluted or the composition is ready for use, the total amount of hyaluronidase in the composition of the disclosure that will be delivered to the patient over the course of an intravenous administration (in one dose), for example over an hour, will contain about 150 USP units (United States Pharmacopeia units) to about 75,000 USP units of hyaluronidase, or about 300 USP units to about 72,500 USP units, or about 450 USP units to about 70,000 USP units, or about 600 USP units to about 67,500 USP units, or about 750 USP units to about 65,000 USP units, or about 1,000 USP units to about

62.500 USP units, or about 1,000 USP units to about 60,000 USP units, or about 1,250 USP units to about 60,000 USP units, or about 1,500 USP units to about 57,500 USP units, or about 2,000 USP units to about 55,000 USP units, or about 2,250 USP units to about 52,500 USP units, or about 2,500 USP units to about 50,000 USP units, or about 3,000 USP units to about 47,500 USP units, or about 3,500 USP units to about 45,000 USP units, or about 4,000 USP units to about 42,500 USP units, or about 4,500 USP units to about 40,000 USP units, or about 5,000 USP units to about

37.500 USP units, or about 7,500 USP units to about 35,000 USP units, or about

1.500 USP units to about 50,000 USP units, or about 10,000 USP units to about 30,000 USP units. In some embodiments, the composition will be formulated to deliver a total of about 15,000 USP units of hyaluronidase to a patient in one dose.

[00020] It should be readily apparent to a person skilled in the art that the concentration of the hyaluronidase in the ready to use as supplied composition or the composition after dilution will be dependent upon the amount of diluent present. For example, 50 ml of a composition of the disclosure that will be administered to a patient over an hour may contain hyaluronidase in a range of about 50 USP units per ml to about 500 USP units per ml, or about 50 USP units per ml to about 450 USP units per ml, or about 50 USP units per ml to about 400 USP units per ml, or about 100 USP units per ml to about 500 USP units per ml, or about 100 USP units per ml to about 400 USP units per ml, or about 200 USP units per ml to about 350 USP units per ml, or about 250 USP units per ml to about 350 USP units per ml. In some embodiments, a composition of the disclosure that will be administered to a patient over about an hour may contain about 300 USP units per ml of hyaluronidase. The amount of hyaluronidase that would be used in a concentrate composition of the disclosure can be readily determined by a person of ordinary skill in the art based on the level of dilution. For example, a concentrate that will be diluted 5 fold, e.g. 10 ml into 40 ml of diluent, would therefore contain hyaluronidase in an amount of about 250 USP units per ml to about 2,500 USP units per ml, while a composition concentrate that will be diluted 50 fold would therefore contain hyaluronidase in an amount of about 2,500 USP units per ml to about 25,000 USP units per ml. For example, in some embodiments, a 10 ml composition which is a concentrate that is to be diluted 5 fold with the addition of 40 ml of diluent will contain about 1,500 USP units of hyaluronidase.

VASODILATORS

[00021] Commonly used vasodilators include, for example, nitroprusside, nitroglycerin and hydralazine. While nitroprusside and nitroglycerin may be administered intravenously and have a fast onset and short duration of action, they are incompatible when combined in a formulation of hyaluronidase as they will degrade the hyaluronidase and drastically shorten the shelf life of the composition. Thus, the compositions of the disclosure must use a vasodilator that is compatible in combination with hyaluronidase. In addition, the vasodilator should not have side effects that are unacceptable in the treatment of conditions resulting from a buildup of vascular plaque. For example, hydralazine is not considered appropriate for the formulation as it produces a reflex stimulation of the heart which increases heart rate and cardiac output and may induce symptoms of angina. Hydralazine may also increase plasma renin, which causes fluid retention, and has common side effects including (>10%) of headache, tachycardia and palpitations. Thus, hydralazine is not considered an acceptable vasodilator for use in the compositions and methods of this disclosure.

[00022] Exemplary vasodilators that may be used in the compositions of the disclosure include those selected from the group consisting of benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, trepostinil and combinations thereof. In some embodiments, the vasodilator is trepostinil.

[00023] The one or more vasodilators in the intravenous composition when ready for administration, e.g., after the concentrate has been diluted for administration, will be present in a range of about 0.005 mg/ml to about 0.1 mg/ml, or about 0.005 mg/ml to about 0.09 mg/ml, or about 0.005 mg/ml to about 0.08 mg/ml, or about 0.005 mg/ml to about 0.07 mg/ml, or about 0.006 mg/ml to about 0.095 mg/ml, or about 0.007 mg/ml to about 0.09 mg/ml, or about 0.008 mg/ml to about 0.085 mg/ml, or about 0.009 mg/ml to about 0.08 mg/ml, or about 0.01 mg/ml to about 0.075 mg/ml, or about 0.02 mg/ml to about 0.07 mg/ml, or about 0.03 mg/ml to about 0.065 mg/ml, or about 0.04 mg/ml to about 0.06 mg/ml, or about 0.05 mg/ml to about 0.075 mg/ml, or about 0.01 mg/ml to about 0.1 mg/ml, or about 0.025 mg/ml to about 0.1 mg/ml, or about 0.05 mg/ml to about 0.1 mg/ml. Generally, the concentration of vasodilator will be set so as to deliver to the patient a total amount of about 50 pg to about 500 pg of vasodilator, or about 50 pg to about 450 pg of vasodilator, or about 50 pg to about 400 pg of vasodilator, or about 50 pg to about 350 pg of vasodilator, or about 50 pg to about 300 pg of vasodilator, or about 50 pg to about 250 pg of vasodilator, or about 50 pg to about 200 pg of vasodilator, or about 60 pg to about 450 pg of vasodilator, or about 65 pg to about 400 pg of vasodilator, or about 70 pg to about 350 pg of vasodilator, or about 80 pg to about 300 pg of vasodilator, or about 90 pg to about 250 mg of vasodilator, or about 75 mg to about 250 mg of vasodilator, or about 100 mg to about 200 mg of vasodilator. For example, the concentration of the vasodilator may be set so that during an hour-long period of IV administration, the patient receives a total dose of 0.125 mg vasodilator, such as, for example, trepostinil.

DILUENTS AND ADJUVANTS

[00024] The diluent used in the composition may be any diluent or combination of diluents that are suitable for intravenous administration. Examples of diluents include, without limitation, Polyethylene Glycols (e.g., PEGs 100 to 1,000, including PEG- 300), 5% dextrose in water, sterile water, and 0.9% sodium chloride in sterile water.

In some embodiments, the diluent is 0.9% sodium chloride in sterile water.

[00025] If desired, the composition may include a preservative or anti -bactericide.

Such adjuvants, however, are not necessary when the pharmaceutical composition is provided in a single use sterile vial, such as for example, a ready to use single use sterile vial or as a concentrate in a 5 ml or 10 ml sterile vial, that is diluted prior to administration to a patient.

FORMULATION

[00026] The pharmaceutical composition may be prepared by mixing the hyaluronidase and the one or more vasodilators in a diluent suitable for intravenous administration.

[00027] In some embodiments, the composition may be a concentrate that is diluted prior to intravenous administration or a composition ready for intravenous administration without further dilution. The concentrate after dilution or the ready to use composition must be suitable for intravenous administration. [00028] In some embodiments, the composition is formulated as a concentrate that, at the time of use, is further diluted with a diluent acceptable for intravenous administration. The diluted concentrate may then be intravenously administered to a patient in need thereof, for example through the use of an IV pump or IV drip over a period of time.

[00029] The amount of hyaluronidase and vasodilator included in the composition will be an amount that will be delivered over a period of time, for example, as described above. Generally, the ratio of hyaluronidase in USP units to vasodilator in micrograms is in a range of about 1500: 1 to about 0.3: 1, or about 150: 1 to about 3:1, or about 6: 1 to about 18: 1, or about 12: l, e.g., USP units of hyaluronidase to micrograms of vasodilator (such as, for example, trepostinil). In some embodiments, the ratio of hyaluronidase in USP units to vasodilator in micrograms is in a range of about 12: 1, e.g., USP units of hyaluronidase to micrograms of vasodilator (such as, for example, trepostinil).

[00030] When formulating a pharmaceutical composition of the disclosure that is provided as a concentrate for further dilution, the amounts of hyaluronidase and vasodilator in the composition will be dependent on the dilution that will be used prior to administration. For example, if the concentrate is a 10 ml aliquot in a sterile vial that will be mixed with 40 ml of additional diluent (thus providing 50 ml of the composition for administration), the concentrate will be formulated to contain five times the concentration of the desired amount in the diluted composition. Thus, the amount of hyaluronidase and vasodilator in the concentrate can readily be calculated by one of ordinary skill based on the amount of each active ingredient that is desired to be administered to the patient. A limiting factor in preparing a concentrate is, for example, that the hyaluronidase and vasodilator must be able to be solubilized in the diluent of the concentrate.

[00031] A person of ordinary skill in the art would understand that generally a formulation for intravenous administration would be prepared such that administration of the formulation intravenously would not change the pH of the blood. As such, the pH of the formulation would depend on the amount to be administered. For example, a formulation for intravenous administration may be formulated at a pH of about 7.2 to about 7.4.

[00032] In some embodiments, a pharmaceutical composition of the present disclosure may be provided in a single vial, for example as a single use sterile vial. In some embodiments, a pharmaceutical composition of the present disclosure may be provided in more than one vial, such as for example, in two single use sterile vials. In some embodiments, a pharmaceutical composition of the present disclosure may be provided in two vials, wherein one vial comprises a vasodilator and at least one diluent and a second vial comprises lyophilized hyaluronidase. A person of ordinary skill in the art would understand how to reconstitute a formulation comprising lyophilized hyaluronidase prior to intravenous administration. Providing hyaluronidase in a lyophilized form may, for example, provide more freedom in shipping and/or improved stability.

METHOD OF TREATMENT

[00033] The pharmaceutical compositions of this disclosure may be administered to a patient in need thereof by intravenous infusion, e.g., using an IV pump or an IV drip. In some embodiments, it is preferred to administer the pharmaceutical composition using an IV pump as this may provide greater control over the administration of the pharmaceutical composition. [00034] In some embodiments, the pharmaceutical composition will be provided to the medical practitioner as a concentrated formulation that will be further diluted prior to intravenous infusion. In some embodiments, the entire vial of a concentrated composition of the disclosure will be added to a given amount of diluent suitable for intravenous administration. For example, a 10 ml vial of a concentrated pharmaceutical composition of the disclosure may be added to a diluent, such as an aqueous saline solution. A person of ordinary skill will understand that the amount of dilution will be dependent on the concentration of the hyaluronidase and vasodilator in the concentrate and the amount of hyaluronidase and vasodilator that the medical practitioner desires to deliver to the patient during the infusion period. The infusion period may range from about 15 minutes to about 4 hours, such as for example, 15 minutes, or 30 minutes, or 45 minutes, or 1 hour, or 1 hour and 15 minutes, or 1 hour and 30 minutes, or 1 hour and 45 minutes, or 2 hours, or 2 hours and 30 minutes, or 3 hours, or 3 hours and 30 minutes, or 4 hours, etc. In some embodiments, the infusion period is about 1 hour. In some embodiments, an infusion of a dose of the pharmaceutical composition of the disclosure may be administered for 1 to 7 days a week over a period of 1 to 8 weeks, or 2 to 6 days over a period of 1 to 5 weeks, or 3 to 5 days a week for a period of 1 to 4 weeks, or 4 to 5 days a week for a period of 2 to 3 weeks.

[00035] In some embodiments, the methods of the present disclosure comprise the step of intravenously administering a pharmaceutical composition of the disclosure to a patient in need thereof, wherein the pharmaceutical composition of the disclosure may be administered in one or more doses during a treatment period. In some embodiments, a pharmaceutical composition of the disclosure may be administered during a treatment period for a total of 1 dose, or 2 doses, or 3 doses, or 4 doses, or 5 doses, or 6 doses, or 7 doses, or 8 doses, or 9 doses, or 10 doses, or 11 doses, or 12 doses, or 13 doses, or 14 doses, or 15 doses, or 16 doses, or 17 doses, or 18 doses, or 19 doses, or 20 doses, or any number therebetween. In some embodiments, a treatment period may be a period of 1 to 8 weeks, or 1 to 5 weeks, or 1 to 4 weeks, or 2 to 3 weeks. For example, in some embodiments, a pharmaceutical composition of the present disclosure is provided as 10 doses over two weeks. For example, in some embodiments, a pharmaceutical composition of the present disclosure is provided as 14 doses over two weeks. Each dose as disclosed herein may be administered daily via a single or multiple infusions.

[00036] The compositions this disclosure may be administered to treat one or more conditions selected from the group consisting of coronary artery disease, carotid artery disease, atherosclerosis, hypertension, kidney disease and diabetic foot syndrome. The combination of the vasodilator with the hyaluronidase is believed to allow the hyaluronidase to work better than without vasodilator as the hyaluronidase in the compositions of the disclosure can access vascular structures that are particularly difficult to treat, such as arterioles and capillaries.

Examples

[00037] A pharmaceutical composition for intravenous infusion was prepared by solubilizing 15,000 USP units per ml of an active form of a human recombinant hyaluronidase (HYLENEX^®) and 0.137 mg of trepostinil in 10 ml of aqueous saline solution. Prior to administration, the concentrated pharmaceutical composition was added to 40 ml of aqueous sterile saline solution, i.e., 0.9 % sodium chloride in sterile water. [00038] The resulting 50 ml pharmaceutical composition containing a concentration of 300 IU/ml hyaluronidase and 2.74 pg/ml of trepostinil was administered to a patient by means of an IV infusion pump over a period of one hour. For each patient treated, the administration was repeated for 10 treatments over a period of 2 to 3 weeks. No more than one treatment was provided to a patient per day. Typically, 5 treatments were given per week over a two-week period. All the patients treated responded well to the treatment.

[00039] Sequences

[00040] SEQ ID NO:l

[00041] LNFRAPPVIP NVPFLWAWNA PSEFCLGKFD EPLDMSLFSF

IGSPRINATG QGVTIFYVDR LGYYPYIDSI TGVTVNGGIP QKISLQDHLD KAKKDITFYM PVDNLGMAVI DWEEWRPTWA RNWKPKDVYK NRSIELVQQQ NVQLSLTEAT EKAKQEFEKA GKDFLVETIK LGKLLRPNHL WGYYLFPDCY NHHYKKPGYN GSCFNVEIKR NDDLSWLWNE STALYPSIYL NTQQSPVAAT LYVRNRVREA IRVSKIPDAK SPLPVFAYTR IVFTDQVLKF LSQDELVYTF GETVALGASG IVIWGTLSIM RSMKSCLLLD NYMETILNPY IINVTLAAKM CSQVLCQEQG VCIRKNWNSS DYLHLNPDNF AIQLEKGGKF TVRGKPTLED LEQFSEKFYC SCYSTLSCKE KADVKDTDAV DVCIADGVCI DAFLKPPMET EEPQIFY

Claims

What is claimed is:

1. A pharmaceutical composition for intravenous administration, the composition comprising a combination of: a. hyaluronidase; b. a vasodilator compatible with the hyaluronidase; and c. at least one diluent, wherein the amount of hyaluronidase and the amount of vasodilator in the composition are in combination effective to reduce vascular plaque after intravenous administration to a patient in need thereof.

2. The pharmaceutical composition of claim 1, wherein the hyaluronidase is selected from the group consisting of bovine hyaluronidase, porcine hyaluronidase, ovine hyaluronidase and human recombinant hyaluronidase.

3. The pharmaceutical composition of claims 1 or 2, wherein the hyaluronidase is human recombinant hyaluronidase produced by genetically engineered Chinese Hamster Ovary (CHO) cells comprising a DNA plasmid encoding for a soluble fragment of human hyaluronidase (PH20).

4. The pharmaceutical composition of any one of claims 1-3, wherein the hyaluronidase is a purified hyaluronidase glycoprotein of SEQ ID NO: 1.

5. The pharmaceutical composition of any one of claims 1-4, wherein the total amount of hyaluronidase in the composition is in a range of about 150 USP units to about 75,000 USP units, or about 750 USP units to about 65,000 USP units, or about 1,000 USP units to about 60,000 USP units, or about 2,000 USP units to about 55,000 USP units, or about 2,500 USP units to about 50,000 USP units, or about 4,500 USP units to about 40,000 USP units, or about 7,500 USP units to about 35,000 USP units, or about 1,500 USP units to about 50,000 USP units, or about 10,000 USP units to about 30,000 USP units.

6. The pharmaceutical composition of any one of claims 1-5, wherein the concentration of hyaluronidase in the pharmaceutical composition is in a range of about 50 USP units per ml to about 500 USP units per ml, or about 100 USP units per ml to about 400 USP units per ml, or about 200 USP units per ml to about 350 USP units per ml, or about 250 USP units per ml to about 350 USP units per ml.

7. The pharmaceutical composition of claim 6, wherein the concentration of hyaluronidase in the pharmaceutical composition is about 300 USP units per ml.

8. The pharmaceutical composition of any one of claims 1-7, wherein the vasodilator is selected from the group consisting of benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, trepostinil and combinations thereof.

9. The pharmaceutical composition of any one of claims 1-8, wherein the vasodilator is trepostinil.

10. The pharmaceutical composition of any one of claims 1-9, wherein the vasodilator is present in the composition in an amount of about 50 pg to about 500 pg, or about 60 pg to about 450 pg, or about 65 pg to about 400 pg, or about 70 pg to about 350 pg, or about 80 pg to about 300 pg, or about 90 pg to about 250 pg, or about 75 pg to about 250 pg, or about 100 pg to about 200 pg.

11. The pharmaceutical composition of claims 8 or 9, wherein the trepostinil in the composition is present in an amount of about 50 pg to about 500 pg, or about 60 pg to about 450 pg, or about 65 pg to about 400 pg, or about 70 pg to about 350 pg, or about 80 pg to about 300 pg, or about 90 pg to about 250 pg, or about 75 pg to about 250 pg, or about 100 pg to about 200 pg.

12. The pharmaceutical composition of any one of claims 1-11, wherein the composition is suitable for treating one or more conditions selected from the group consisting of coronary artery disease, carotid artery disease, atherosclerosis, hypertension, kidney disease and diabetic foot syndrome.

13. The pharmaceutical composition of any one of claims 1-12, wherein the composition is a concentrate for dilution prior to intravenous administration or a ready to use composition.

14. The pharmaceutical composition of any one of claims 1-13, wherein the composition is administered by intravenous infusion.

15. A method for treating one or more conditions resulting from a buildup of vascular plaque in a patient, the method comprising the step of intravenously administering the pharmaceutical composition of any one of claims 1-14 to the patient in need thereof by IV pump or IV drip.

16. The method of claim 15, wherein the composition is administered to the patient for a time period of about 15 minutes to 4 hours, or about 30 minutes to about 4 hours, or about 30 minutes to about 3 hours and 30 minutes, or about 30 minutes to about 3 hours, or about 30 minutes to about 2 hours and 30 minutes, or about 45 minutes to about 2 hours, or about 45 minutes to about 1 hour 30 minutes, or about 1 hour.

17. The method of claim 15 or 16, wherein the one or more conditions are selected from the group consisting of coronary artery disease, carotid artery disease, atherosclerosis, hypertension, kidney disease and diabetic foot syndrome.

18. The method of any one of claims 15-17, wherein the hyaluronidase is selected from the group consisting of bovine hyaluronidase, porcine hyaluronidase, ovine hyaluronidase and human recombinant hyaluronidase.

19. The method of any one of claims 15-18, wherein the hyaluronidase is human recombinant hyaluronidase produced by genetically engineered Chinese Hamster Ovary (CHO) cells comprising a DNA plasmid encoding for a soluble fragment of human hyaluronidase (PH20).

20. The method of any one of claims 15-19, wherein the hyaluronidase is a purified hyaluronidase glycoprotein of SEQ ID NO: 1.

21. The method of any one of claims 15-20, wherein the vasodilator is selected from the group consisting of benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, trepostinil and combinations thereof.

22. The method of any one of claims 15-21, wherein the vasodilator is trepostinil.

23. The method of any one of claims 15-22, wherein the composition is administered to the patient for 1 to 7 days a week, or 2 to 6 days a week, or 3 to 5 days a week, or 4 to 5 days a week.

24. The method of any one of claims 15-23, wherein the composition is administered to the patient during a treatment period for a total of 1 dose, or 2 doses, or 3 doses, or 4 doses, or 5 doses, or 6 doses, or 7 doses, or 8 doses, or 9 doses, or 10 doses, or 11 doses, or 12 doses, or 13 doses, or 14 doses, or 15 doses, or 16 doses, or 17 doses, or 18 doses, or 19 doses, or 20 doses.

25. The method of claim 24, wherein the treatment period is 1 to 8 weeks, or 1 to 5 weeks, or 1 to 4 weeks, or 2 to 3 weeks.

26. Use of the pharmaceutical composition of any one of claims 1-14 for the treatment of one or more conditions resulting from a buildup of vascular plaque in a patient.

27. A pharmaceutical composition of any one of claim 1-14 for use in the treatment of one or more conditions resulting from a buildup of vascular plaque in a patient.