JP2019510002A - Long-acting pharmaceutical composition of protease inhibitor - Google Patents

Abstract

Disclosed herein are long acting pharmaceutical compositions for treating or preventing human immunodeficiency virus (HIV) infection. The pharmaceutical composition comprises a suspension of a lysine-based aspartyl protease inhibitor or salt thereof, a surface modifier, and a pharmaceutically acceptable carrier; wherein a lysine-based aspartyl protease inhibitor or The salt has an average effective particle size of less than about 500 nm. Also disclosed are methods for treating or preventing HIV infection with a pharmaceutical composition.

Description

  The present invention relates to novel pharmaceutical compositions of protease inhibitors that provide a long-acting effect in inhibiting the activity of HIV aspartyl protease, which is advantageously used to develop new approaches in the treatment of HIV. The present invention also generally relates to a method for treating HIV.

  Human immunodeficiency virus (HIV) causes acquired immune deficiency syndrome (AIDS) through infection of specialized cells of the immune system carrying the CD4 receptor. HIV retroviruses grow in these cells, especially so-called helper T cells, and kill them in the process. The body has the ability to regenerate T helper cells to some extent, but after years of continuous cell destruction by HIV and counterattack by the immune system, the virus eventually emerges as the winner of the battle. Progressive destruction of T helper cells results in weakening of the immune system, which in turn opens the door to opportunistic pathogens. When this happens, people infected with HIV begin to show clinical symptoms. If left unconfirmed, HIV infection will cause death within a few years.

  In order to grow in infected cells, HIV requires three major enzymes that are carried within the viral particle. Therefore, these three enzymes, reverse transcriptase, protease and integrase are ideal targets for antiviral therapy. Of these, reverse transcriptase was the first enzyme targeted by the pharmaceutical industry. Viral protease inhibitors have been developed very recently and their use as AIDS therapeutics has only just started in 1996. While the development of reverse transcriptase and protease inhibitors has significantly improved the survival and quality of life of HIV-infected patients, their use has been associated with undesirable side effects such as anemia, neurotoxicity, myelosuppression and lipodystrophy. cause. Most of the currently available anti-protease agents are large molecules with limited ability to cross the blood brain barrier.

  Several new compounds without these disadvantages have been developed to treat HIV infection and fight resistant virus strains. PCT International Patent Application PCT / CA02 / 00190 (Stranix et al.) Published under WO02 / 064551 disclosed protease inhibitors based on amino acid derivatives. More particularly, this patent application includes N-amino acid substituted L-lysine derivatives (and analogs) having aspartyl protease inhibitory properties. Several alternative compounds with such properties have also been provided. For example, US Pat. No. 6,632,816 B1 disclosed a new class of aromatic derivatives having aspartyl protease inhibitory properties and their biological applications in the treatment of HIV infection.

  Currently, long acting antiretroviral drugs are under development for the treatment of chronic HIV infection. Long-acting medicines may provide an attractive option for HIV patients facing the lifetime of anti-HIV treatment. These agents have the advantage of being more convenient and potentially improving patient compliance. However, none of the previous studies have provided good long acting pharmaceutical compositions of protease inhibitors for treating HIV infection.

Summary of the Invention The present invention provides a novel approach for the treatment or prevention of HIV infection. In various embodiments of the invention, novel long acting pharmaceutical compositions of protease inhibitors and methods for treating HIV infection with long acting pharmaceutical compositions are provided.

  In one aspect, the present invention provides a pharmaceutical composition comprising a suspension of a lysine-based aspartyl protease inhibitor or salt thereof, a surface modifier, and a pharmaceutically acceptable carrier; The lysine-based aspartyl protease inhibitor or salt thereof has an average effective particle size of less than about 500 nm.

  In some preferred embodiments of the invention, the average effective particle size of the lysine-based aspartyl protease inhibitor or salt thereof is preferably less than about 300 nm, more preferably less than about 200 nm, and most preferably from about 100 nm to about 200 nm. It is.

  In one aspect, the invention is for administration by intramuscular or subcutaneous injection comprising a suspension of a lysine-based aspartyl protease inhibitor or salt thereof, a surface modifier, and a pharmaceutically acceptable carrier. Wherein the lysine-based aspartyl protease inhibitor or salt thereof has an average effective particle size of less than about 500 nm.

  In a further aspect, the present invention provides a method for long-term treatment or prevention of HIV infection. The method comprises administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of the present invention by intramuscular or subcutaneous injection from once a week to once a month.

  In one or more embodiments, the dosage of the suspension is from about 5 to about 65 mg / kg of the subject's body weight.

  In yet another aspect, the present invention relates to a lysine-based aspartyl protease for the manufacture of a medicament for the treatment or prevention of HIV infection by intramuscular or subcutaneous injection once a week to once a month. Provided is the use of a suspension of an inhibitor or salt thereof, a surface modifier, and a pharmaceutically acceptable carrier; wherein the lysine-based aspartyl protease inhibitor or salt thereof has an average of less than about 500 nm Has an effective particle size.

  In one or more embodiments, the medicament is administered once a month.

The foregoing summary, as well as the following detailed description of the present invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. However, it should be understood that the invention is not limited to such embodiments.
In the drawing:

Fig. 2 shows the PK profile of TMB-607 in humans orally administered with TMB-657. 2 shows the PK profile of TMB-607 in rats administered TMB-607 in the form of microparticles (2470 nm) and nanosuspension (240 nm), respectively. 2 shows plasma levels of TMB-607 in Beagle dogs after subcutaneous (SC) and intramuscular (IM) injections of TMB-607, respectively. 2 shows plasma levels of TMB-607 in monkeys administered TMB-607 in the form of nanosuspensions of different particle sizes (240 nm and 113 nm).

Detailed Description of the Invention The present invention represents for the first time a new approach for preventing or treating HIV infection with long acting pharmaceutical compositions for administration by intramuscular or subcutaneous injection.

  Accordingly, the present invention provides a long acting for treating or preventing HIV infection comprising a suspension of a lysine-based aspartyl protease inhibitor or salt thereof, a surface modifier and a pharmaceutically acceptable carrier. Wherein a lysine-based aspartyl protease inhibitor or salt thereof is an average of less than about 500 nm, preferably less than about 300 nm, more preferably less than about 200 nm, most preferably from about 100 nm to about 200 nm. Has an effective particle size.

Lysine-based aspartyl protease inhibitors
Ambrilia Biopharma Inc. has developed a lysine-based aspartyl protease inhibitor with the activity of an HIV-1 protease inhibitor as described in US Pat. No. 6,632,816 (incorporated herein by reference in its entirety). We are developing.

[式中、
nは、3または4であり、
XおよびYは、同一もしくは異なって、H、1〜6個の炭素原子の直鎖アルキル基、3〜6個の炭素原子の分枝鎖アルキル基、3〜6個の炭素原子のシクロアルキル基、F、Cl、Br、I、-CF₃、-OCF₃、-CN、-NO₂、-NR₄R₅、-NHCOR₄、-OR₄、-SR₄、-COOR₄、-COR₄、and -CH₂OHからなる群から選択されるか、またはXおよびYは、一緒になって、式：-OCH₂O-のメチレンジオキシ基および式：-OCH₂CH₂O-のエチレンジオキシ基からなる群から選択されるアルキレンジオキシ基を規定し、
R₁は、1〜6個の炭素原子の直鎖アルキル基、3〜6個の炭素原子の分枝鎖アルキル基、そのシクロアルキル部分において3〜6個の炭素原子およびそのアルキル部分において1〜3個の炭素原子を有するシクロアルキル基からなる群から選択され、
R₂は、H、1〜6個の炭素原子の直鎖アルキル基、3〜6個の炭素原子の分枝鎖アルキル基、3〜6個の炭素原子のシクロアルキル基、および式：R_2A-CO-の基(ここで、R_2Aは、1〜6個の炭素原子の直鎖もしくは分枝鎖アルキル基、3〜6個の炭素原子を有するシクロアルキル基、そのシクロアルキル部分において3〜6個の炭素原子およびそのアルキル部分において1〜3個の炭素原子を有するシクロアルキルアルキル基、1〜6個の炭素原子のアルキルオキシ基、テトラヒドロ-3-フラニルオキシ、-CH₂OH、-CF₃、-CH₂CF₃、-CH₂CH₂CF₃、ピロリジニル、ピペリジニル、4-モルホリニル、CH₃O₂C-、CH₃O₂CCH₂-、Acetyl-OCH₂CH₂-、HO₂CCH₂-、3-ヒドロキシフェニル、4-ヒドロキシフェニル、4-CH₃OC₆H₄CH₂-、CH₃NH-、(CH₃)₂N-、(CH₃CH₂)₂N-、(CH₃CH₂CH₂)₂N-、HOCH₂CH₂NH-、CH₃OCH₂O-、CH₃OCH₂CH₂O-、C₆H₅CH₂O-、2-ピロリル、2-ピリジル、3-ピリジル、4-ピリジル-、2-ピラジニル、2-キノリル、3-キノリル、4-キノリル、1-イソキノリル、3-イソキノリル、2-キノキサリニル、
式：

のフェニル基、

からなる群から選択されるピコリル基、

からなる群から選択されるピコリルオキシ基、

からなる群から選択される置換ピリジル基、

からなる群から選択される基、
(ここで、X’およびY’は、同一もしくは異なって、H、1〜6個の炭素原子の直鎖アルキル基、3〜6個の炭素原子の分枝鎖アルキル基、3〜6個の炭素原子のシクロアルキル基、F、Cl、Br、I、-CF₃、-NO₂、-NR₄R₅、-NHCOR₄、-OR₄、-SR₄、-COOR₄、-COR₄ およびCH₂OHからなる群から選択される(ここで、R₄およびR₅は、同一もしくは異なって、H、1〜6個の炭素原子の直鎖アルキル基、3〜6個の炭素原子の分枝鎖アルキル基、3〜6個の炭素原子のシクロアルキル基からなる群から選択される))からなる群から選択され、
R₃は、
式(IV)：

のジフェニルメチル基、
式(V)：

のナフチル-1-CH₂-基、
式(VI)：

のナフチル-2-CH₂-基、
式(VII)：

のビフェニルメチル基、および
式(VIII)：

のアントリル-9-CH₂-基からなる群から選択される]
で示される構造を有し、式(I)で示される化合物が、アミノ基を含む場合、その医薬的に許容されるアンモニウム塩が包含される。 As disclosed in US Pat. No. 6,632,816, the compound has the formula (I):

[Where
n is 3 or 4,
X and Y are the same or different, H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms , F, Cl, Br, I, -CF ₃ , -OCF ₃ , -CN, -NO ₂ , -NR ₄ R ₅ , -NHCOR ₄ , -OR ₄ , -SR ₄ , -COOR ₄ , -COR ₄ , It is selected from the group consisting of and -CH ₂ OH, or X and Y together formula: -OCH ₂ O-methylene dioxy group and the formula: -OCH ₂ CH ₂ O- of ethylene di Defining an alkylenedioxy group selected from the group consisting of oxy groups;
R ₁ is a straight chain alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, 3 to 6 carbon atoms in its cycloalkyl moiety and 1 to 1 in its alkyl moiety. Selected from the group consisting of cycloalkyl groups having 3 carbon atoms;
R ₂ is H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and the formula: R _2A A group of --CO--, wherein R _2A is a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, 3 to 6 cycloalkylalkyl group having 1-3 carbon atoms in the carbon atoms and the alkyl moiety thereof, 1 to 6 alkyl group carbon atoms, tetrahydro-3-furanyloxy, -CH ₂ OH, -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , pyrrolidinyl, piperidinyl, 4-morpholinyl, CH ₃ O ₂ C-, CH ₃ O ₂ CCH _2- , Acetyl-OCH ₂ CH _2- , HO ₂ CCH ₂ -, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-CH ₃ OC ₆ H ₄ CH _2- , CH ₃ NH-, (CH ₃ ) ₂ N-, (CH ₃ CH ₂ ) ₂ N-, (CH ₃ CH ₂ CH ₂ ) ₂ N-, HOCH ₂ CH ₂ NH-, CH ₃ OCH ₂ O-, CH ₃ OCH ₂ CH ₂ O-, C ₆ H ₅ CH ₂ O-, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2 -Quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl,
formula:

A phenyl group of

A picolyl group selected from the group consisting of:

A picolyloxy group selected from the group consisting of

A substituted pyridyl group selected from the group consisting of

A group selected from the group consisting of
(Wherein X ′ and Y ′ are the same or different, H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, 3 to 6 carbon atoms; cycloalkyl group having a carbon, F, Cl, Br, I , -CF 3, -NO 2, -NR 4 R 5, -NHCOR 4, -OR 4, -SR 4, -COOR 4, -COR 4 and CH Selected from the group consisting of ₂ OH, wherein R ₄ and R ₅ are the same or different and are H, a straight chain alkyl group of 1 to 6 carbon atoms, a branch of 3 to 6 carbon atoms Selected from the group consisting of chain alkyl groups, selected from the group consisting of cycloalkyl groups of 3 to 6 carbon atoms)),
R ₃ is
Formula (IV):

Diphenylmethyl group of
Formula (V):

A naphthyl-1-CH ₂ group,
Formula (VI):

A naphthyl-2-CH ₂ -group of
Formula (VII):

And the biphenylmethyl group of formula (VIII):

Selected from the group consisting of anthryl-9-CH ₂ -groups]
When the compound represented by the formula (I) contains an amino group, a pharmaceutically acceptable ammonium salt thereof is included.

の化合物である。 As described in US Pat. No. 6,632,816, one particular embodiment of the compound is of formula (IIa):

It is a compound of this.

の構造を有する、PL-100と呼ばれる化合物(以下、TMB-607と称する)が、HIV-1プロテアーゼの阻害において効果的かつ選択的であり、良好な交差耐性プロファイルを有することが確認された。 Of the compounds of formula (IIa), formula (IIb):
IIb

It was confirmed that a compound called PL-100 (hereinafter referred to as TMB-607) having the following structure is effective and selective in inhibiting HIV-1 protease and has a good cross-resistance profile.

  Antiviral studies have confirmed that TMB-607 is effective and selective in inhibiting HIV-1 protease. In cross-resistance studies against 63 PI resistant strains, TMB-607 was also found to show a lower level of reduced sensitivity than any of the approved protease inhibitors (PIs), in the treatment of experienced patients It shows the potential for good activity against existing PI resistant viruses. A 48 week resistance selection test was performed by increasing the concentration of TMB-607 against laboratory adapted virus in vitro. Four mutations in the protease open reading frame were selected. Site-directed mutagenesis studies indicate that a single mutation did not result in significant resistance to TMB-607 in vitro.

  However, TMB-607 has poor solubility and is not suitable for human medicine. Therefore, a phosphorylated prodrug called TMB-657 (formerly called PPL-100) with improved solubility and pharmacokinetic properties was developed.

  In the present invention, a novel pharmaceutical composition of a lysine-based aspartyl protease inhibitor or a salt thereof, particularly TMB-607, was developed to provide a long-acting effect in the treatment or prevention of HIV infection. The composition can be administered once a week, and even once a month.

The term pharmaceutical composition "pharmaceutically effective amount" refers to an amount effective in treating HIV infection in a patient. As used herein, “pharmaceutically effective amount” is interpreted as an amount that provides a desired therapeutic effect at a dose, or at any dose, or by route, or alone or in combination with other therapeutic agents. Can be done. In the case of the present invention, a “pharmaceutically effective amount” is an HIV (HIV-1 and HIV-2 and related viruses (eg, HTLV-I and HTLV-II, and simian immunodeficiency virus)) infection cycle. It can be understood as an amount that has an inhibitory effect (eg, inhibition of replication, reinfection, maturation, budding, etc.) and in any organism that relies on aspartyl protease for life cycle.

  Furthermore, the present invention uses novel compounds of Formula I, Formula IIa and IIb derived from L-lysine or L-lysine derivatives (and lower homologues thereof (ie, ornithine)), such as HIV aspartyl protease Protection from HIV infection is provided by providing a pharmaceutical composition that inhibits the aspartyl protease.

  The terms “HIV protease” and “HIV aspartyl protease” are used interchangeably and refer to an aspartyl protease encoded by human immunodeficiency virus type 1 or type 2. In a preferred embodiment of the invention, these terms refer to human immunodeficiency virus type 1 aspartyl protease.

  The term “therapeutically effective amount” refers to an amount effective to treat or prevent HIV infection in a subject or patient.

  The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier or adjuvant that can be administered to a patient with a compound of the present invention and that does not destroy its pharmacological activity.

  The compounds of the present invention include pharmaceutically acceptable derivatives of compounds of formula I (and compounds of formulas II, IIa, IIb and IIc) and applicable pharmaceutically acceptable salts thereof.

  As used herein, the term “pharmaceutically acceptable derivative” refers to a compound of the invention or an antiviral active metabolite or residue thereof upon administration to a compound of the invention or recipient. Pharmaceutically acceptable salts, esters, salts of such esters of any other compound capable of providing (directly or indirectly).

  According to the present invention, pharmaceutically acceptable salts of the compounds of the present invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of such acid salts include: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphoric acid Salt, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl hydrogensulfate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate , Hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonic acid Salt, 2-naphthyl sulfonate, nicotinate, nitrate, oxalate, pamoate, pectate, perchlorate, persulfate, 3-phenylpropionate, lithium , Picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate.

  With respect to the number of carbon atoms, the description of a range of 1 to 6 carbon atoms is used herein to describe the number of any individual carbon atom, as well as, for example, 1 carbon atom, 3 carbon atoms, 4-6 It should be understood as incorporating sub-ranges such as carbon atoms.

  In accordance with the present invention, a long acting pharmaceutical composition comprises a suitable particle size lysine-based aspartyl protease inhibitor or salt thereof, a suitable surface modifier, and one or more suitable pharmaceutically. It can be prepared by any commonly used known method by mixing with an acceptable carrier.

  In the present invention, the surface modifier is selected from the group consisting of poloxamer, α-tocopheryl polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid ester, and phospholipid. Preferably, the surface modifier is poloxamer 188, poloxamer 407, d-α-tocopheryl polyethylene glycol 1000 succinate (simply TPGS or vitamin E TPGS), supported by the examples shown in Table 1. Selected from the group consisting of Tween 80 and distearoylphosphatidylethanolamine-poly (ethylene glycol) (DSPE-PEG).

Methods of Treatment and Prevention According to the present invention, the long acting pharmaceutical compositions disclosed herein are used for the treatment and / or prevention of HIV infection and prevention of HIV transmission in a subject.

  The term “treatment” of HIV infection refers to effective inhibition of HIV infection, such as delaying onset, slowing progression, reducing viral load, and / or ameliorating symptoms caused by HIV infection.

The term “prevention” of HIV infection means that the onset of HIV infection is delayed and / or the incidence or likelihood of HIV infection is reduced or eliminated.

  The term “prevention” of HIV transmission refers to the incidence or likelihood that HIV is transmitted from one individual to another (eg, from pregnancy, labor or labor, or breastfeeding, from HIV positive women to children; or Means from HIV positive subjects to HIV negative partners).

  The term “subject” or “patient” refers to any primate subject, including human and non-human subjects (eg, rhesus monkey subjects).

  In order to treat and / or prevent HIV infection, a therapeutic amount of the pharmaceutical composition disclosed herein is administered to a subject in need.

  The term “therapeutically effective amount” means the dose necessary to achieve inhibition of HIV infection in order to treat and / or prevent HIV infection. The dosage of the antibody depends on the disease state and other clinical factors such as, for example, the subject's weight and condition, the subject's response to treatment. The exact dosage, which is therapeutically effective and not harmful, can be determined by one skilled in the art. In one embodiment of the invention, a suitable dose of a long acting pharmaceutical composition for intramuscular or subcutaneous administration to an adult is about 5 to about once a week or once a month. It is in the range of 65 mg / kg body weight of the subject.

According to long-acting effects present invention in the pharmaceutical composition of the present invention, in the embodiment, TMB-607 which is an example of a lysine base aspartyl protease inhibitors, surface modifying agents and a pharmaceutically acceptable carrier The suspension has been confirmed to provide a long acting effect, wherein the lysine-based aspartyl protease inhibitor or salt thereof has an average effective particle size of less than about 500 nm. As shown in Example 3, the plasma level of TMB-607 in the group treated with TMB-607 in the form of nanosuspension (247 nm) by subcutaneous administration is TMB-607 in the form of microparticles (2470 nm). Persisted for more than 14 days compared to the group treated with (see Figure 2). This indicated that nano-sized TMB-607 could prolong plasma levels above the protein binding regulatory EC50 for 14 days, whereas TMB-607 microparticles were not.

  Also, in Example 4, animals after treatment with a single intramuscular or subcutaneous injection of TMB-607 in the form of a nanosuspension were confirmed to have increased plasma levels of TMB-607 ( (See Figure 3). Furthermore, in Example 5, both 214 nm and 113 nm particle sizes could prolong plasma levels, with the smaller size of TMB-607 (113 nm) having higher plasma levels and longer shelf life. Proven.

Example 1
Preparation of TMB-607 Nanosuspension To prepare nanosuspension by wet ball milling, TMB-607 was used at a drug to polymer ratio (D / P ratio, w / w) from 1: 1 to 7: 1. Was added to an aqueous polymer solution having The suspension mixture was then poured into a Delta Vita 15-300 (DV-15, Netzsch Premier Technologies, USA-Exton, PA) partially filled with 0.1-3 mm ZrO ₂ grinding beads in a grinding chamber. The suspension mixture was milled at various speeds for about 6 hours to 7 days until the average particle size reached the submicron range. When the wet ball milling was complete, the drug concentration of the nanonized suspension mixture was adjusted by WFI. After the concentration adjustment, an isotonic agent was added to adjust the osmotic pressure of the suspension mixture to 300 mOsm / kg. The final concentration of TMB-607 for injectable suspension DP ranged from 20 mg / ml to 400 mg / ml. The particle size of the various formulations analyzed by a dynamic light scattering device (Zetasizer Nano S, Malvern) was about 100 nm to 500 nm. The formulation of the obtained TMB-607 nanosuspension is summarized in Table 1 below.
Table 1: Composition, concentration and particle size of TMB-607 nanosuspension

Example 2
Pharmacokinetic study of oral dosage form TMB-657 A single dose escalation study of the initial human dose of oral formulation TMB-657 was conducted at doses of 300, 600 and 1200 mg. Six subjects received a single dose of TMB-657. A clinical pharmacokinetic profile of TMB-607 was obtained in single dose escalating patients of TMB-657 in relation to its protein-binding regulated antiviral activity (EC50 = 23 ng / ml). As shown in FIG. 1, a single oral TMB-657 dose was able to maintain TMB-607 plasma levels above the effect level (protein binding EC50, 23 ng / ml) for 24 hours. [Kazmierski, Antiviral drugs: from basic discovery through clinical trials, Chapter 2 Page 19, John Wiley & Sons, Inc, 2011.]

Example 3
Pharmacokinetic study of TMB-607 in the form of microparticles and nanosuspensions This study shows that injectable formulations of nanotized TMB-607 provide stable plasma levels for long periods (more than a month) Demonstrated. In the rat study, TMB-607 in the form of microparticles (2470 nm) and nano (240 nm) suspension was administered subcutaneously at doses of 16.7 and 23.5 mg / kg, respectively. The results are shown in FIG. 2, but nano-sized TMB-607 can prolong plasma levels more than the protein binding regulatory EC50 for 14 days, whereas TMB-607 microparticles cannot prolong plasma levels. Indicated. Furthermore, dramatic high Cmax is observed in groups treated with TMB-607 in the form of microparticles at an early time and will cause serious side effects on the human body. In contrast, TMB-607 in the form of nanosuspension showed a sustained release profile during the study period.

Example 3
Comparison between intramuscular and subcutaneous injection A dog study was conducted to compare the pharmacokinetics of TMB-607 after a single intramuscular or subcutaneous injection of nanosuspension. Each treatment group consisted of 3 male beagle dogs at a dose of 60 mg / kg. The particle size used in this study was approximately 150 nm and plasma levels of TMB-607 were monitored for 6 weeks. As shown in Figure 3, there was no significant difference in AUC0-t values between dogs treated with 60 mg / kg TMB-607 by two routes of administration (subcutaneous and intramuscular administration) The Cmax value for the intramuscular route was higher than the Cmax value for the subcutaneous route.

Example 5
In TMB-607 plasma levels monkey pharmacokinetic study in monkeys administered a nanosuspension of different particle sizes, a nanosuspension of TMB-607 of different particle sizes of 214nm and 113 nm, respectively, monkey Injected. Each treatment group consisted of 3 monkeys at a dose of 60 mg / kg. FIG. 5 shows the plasma levels of TMB-607 monitored for 4 weeks. Comparing the administration of different particle sizes of TMB-607 at 60 mg / kg, both the AUC0-t and t1 _{/ 2} generally increased while the particle size of the TMB-607 nanosuspension decreased. The results are shown in FIG. 4 and show that the smaller size of TMB-607 particles has higher plasma levels and longer shelf life.

CONCLUSION The present invention provides suspensions of lysine-based aspartyl protease inhibitors or salts thereof, surface modifiers, and pharmaceutically acceptable carriers; wherein lysine-based aspartyl protease inhibitors or The salt has an average effective particle size of less than about 500 nm and can be developed into a long acting pharmaceutical composition for the treatment or prevention of HIV infection.

Claims (14)

  Long-acting for treating or preventing human immunodeficiency virus (HIV) infection, including suspensions of lysine-based aspartyl protease inhibitors or salts thereof, surface modifiers and pharmaceutically acceptable carriers A pharmaceutical composition wherein the lysine-based aspartyl protease inhibitor or salt thereof has an average effective particle size of less than about 500 nm.   The composition of claim 1, wherein the lysine-based aspartyl protease inhibitor or salt thereof has an average effective particle size of less than about 300 nm.   2. The composition of claim 1, wherein the lysine-based aspartyl protease inhibitor or salt thereof has an average effective particle size of less than about 200 nm.   2. The composition of claim 1, wherein the lysine-based aspartyl protease inhibitor or salt thereof has an average effective particle size of about 100 nm to about 200 nm.   The composition of claim 1, wherein the surface modifier is selected from the group consisting of poloxamer, α-tocopheryl polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid ester, and phospholipid.   Surface modifiers include poloxamer 188, poloxamer 407, d-α-tocopheryl polyethylene glycol 1000 succinate (simply TPGS or vitamin E TPGS), Tween 80 and distearoylphosphatidylethanolamine-poly (ethylene glycol) (DSPE The composition of claim 1 selected from the group consisting of -PEG). Lysine-based aspartyl protease inhibitors have the formula (I):

[Where
n is 3 or 4,
X and Y are the same or different, H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms , F, Cl, Br, I, -CF ₃ , -OCF ₃ , -CN, -NO ₂ , -NR ₄ R ₅ , -NHCOR ₄ , -OR ₄ , -SR ₄ , -COOR ₄ , -COR ₄ , It is selected from the group consisting of and -CH ₂ OH, or X and Y together formula: -OCH ₂ O-methylene dioxy group and the formula: -OCH ₂ CH ₂ O- of ethylene di Defining an alkylenedioxy group selected from the group consisting of oxy groups;
R ₁ is a straight chain alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, 3 to 6 carbon atoms in its cycloalkyl moiety and 1 to 1 in its alkyl moiety. Selected from the group consisting of cycloalkyl groups having 3 carbon atoms;
R ₂ is H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and the formula: R _2A A group of --CO--, wherein R _2A is a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, 3 to 6 cycloalkylalkyl group having 1-3 carbon atoms in the carbon atoms and the alkyl moiety thereof, 1 to 6 alkyl group carbon atoms, tetrahydro-3-furanyloxy, -CH ₂ OH, -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , pyrrolidinyl, piperidinyl, 4-morpholinyl, CH ₃ O ₂ C-, CH ₃ O ₂ CCH _2- , Acetyl-OCH ₂ CH _2- , HO ₂ CCH ₂ -, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-CH ₃ OC ₆ H ₄ CH _2- , CH ₃ NH-, (CH ₃ ) ₂ N-, (CH ₃ CH ₂ ) ₂ N-, (CH ₃ CH ₂ CH ₂ ) ₂ N-, HOCH ₂ CH ₂ NH-, CH ₃ OCH ₂ O-, CH ₃ OCH ₂ CH ₂ O-, C ₆ H ₅ CH ₂ O-, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2 -Quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl,
formula:

A phenyl group of

A picolyl group selected from the group consisting of:

A picolyloxy group selected from the group consisting of

A substituted pyridyl group selected from the group consisting of

A group selected from the group consisting of
(Wherein X ′ and Y ′ are the same or different, H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, 3 to 6 carbon atoms; cycloalkyl group having a carbon, F, Cl, Br, I , -CF 3, -NO 2, -NR 4 R 5, -NHCOR 4, -OR 4, -SR 4, -COOR 4, -COR 4 and CH Selected from the group consisting of ₂ OH, wherein R ₄ and R ₅ are the same or different and are H, a straight chain alkyl group of 1 to 6 carbon atoms, a branch of 3 to 6 carbon atoms Selected from the group consisting of chain alkyl groups, selected from the group consisting of cycloalkyl groups of 3 to 6 carbon atoms)),
R ₃ is
Formula (IV):

Diphenylmethyl group of
Formula (V):

A naphthyl-1-CH ₂ group,
Formula (VI):

A naphthyl-2-CH ₂ -group of
Formula (VII):

And the biphenylmethyl group of formula (VIII):

Selected from the group consisting of anthryl-9-CH ₂ -groups]
The composition according to claim 1, wherein when the compound represented by formula (I) contains an amino group, a pharmaceutically acceptable ammonium salt thereof is included. A lysine-based aspartyl protease inhibitor has the formula (IIa):

The composition of Claim 7 which has a structure shown by these. A lysine-based aspartyl protease inhibitor has the formula (IIb):
IIb

The composition of Claim 8 which is TMB-607 which has a structure shown by these.   The pharmaceutical composition according to claim 1, which is used for administration by intramuscular or subcutaneous injection.   A method for long-term treatment or prevention of HIV infection, wherein a subject in need thereof is treated with a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 10 by intramuscular or subcutaneous injection. Administering once a week to once a month.   12. The method of claim 11, wherein the dosage of the suspension is from about 5 to about 65 mg per kg body weight of the subject.   Lysine-based aspartyl protease inhibitors or salts thereof, surface modifiers for the manufacture of a medicament for the treatment or prevention of HIV infection by intramuscular or subcutaneous injection once a week to once a month And a pharmaceutically acceptable carrier suspension, wherein the lysine-based aspartyl protease inhibitor or salt thereof has an average effective particle size of less than about 500 nm.   14. Use according to claim 13, wherein the suspension is a suspension according to any one of claims 2-10.

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